2-((5-(5-Methyl-2-phenyl-1H-imidazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-phenylethan-1-one

Abstract

A promising imidazole compound was synthesized through the following route. The reaction of 5-methyl-2-phenyl-1H-imidazole-4-carbohydrazide (1) with carbon disulfide and potassium hydroxide in ethanol (80%) afforded potassium salt (2). Refluxing of (2) with phenacyl bromide (3) in ethanol/water (1:1) gave 2-((5-(5-methyl-2-phenyl-1H-imidazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-phenylethan-1-one (4) in a 76% yield. The structure of the title heterocycle (4) was confirmed by single-crystal X-ray diffraction and nuclear magnetic resonance.

1. Introduction

Hydrazide derivatives display a wide variety of biological activities. For example, they have antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antiviral, and antiprotozoal activities [1,2,3].

Imidazole is the basic core of some natural products such as histidine-, purine-, histamine and DNA-based structures [4].

Imidazole compounds showed different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities [5,6,7,8]. In addition, the 1,3,4-oxadiazole nucleus is a biologically imperative scaffold that possesses numerous biological activities, especially in the treatment of cancer disease [9,10,11].

Therefore, the current work reports the synthesis of imidazole containing 1,3,4-oxadiazole moiety using a simple procedure. Recently, the synthesis and structure elucidation of new heterocycles were reported [12,13,14,15].

2. Results and Discussion

2.1. Synthesis

The stirring of 5-methyl-2-phenyl-1H-imidazole-4-carbohydrazide (1) with potassium hydroxide and carbon disulfide in ethanol (80%) gave potassium 2-(5-methyl-2-phenyl-1H-imidazole-4-carbonyl)hydrazine-1-carbodithioate (3). Refluxing of the potassium salt (2) with phenacyl bromide (3) in aqueous ethanol (1:1) for 3 h gave 2-((5-(5-methyl-2-phenyl-1H-imidazol-4-yl)-1,3,4-oxadiazol-2-yl)thio)-1-phenylethan-1-one (4) (Scheme 1). Crystallization of the solid obtained from dimethylformamide (DMF) gave 4 in a 76% yield.

Scheme 1. Synthesis of heterocycle 4.

2.2. NMR Spectroscopy

The ¹H NMR spectrum of 4 showed the methylene protons (CH₂) as a singlet signal at 5.11 ppm and the presence of an exchangeable singlet signal that appeared at 12.97 ppm due to the NH proton. The ¹³C NMR spectrum of 4 showed that the methylene carbon (CH₂) appeared at (40.1 ppm), while the C=O carbon appeared at 193.2 ppm.

2.3. Crystal Structure Description

The title compound (4) crystalized in a monoclinic system with the P2/c space group and possessed four molecules in the unit cell. The crystal structure (Figure 1) was comprised mainly from 1,3,4-oxadiazole, 5-methyl-1H-imidazole and mercaptoacetaldehyde moieties attached with phenyl rings at the terminals.

Figure 1. A view of the structure of the title compound, showing the atom-labelling scheme. Displacement ellipsoids are drawn at a 50% probability level.

In general, the molecule geometry is in good agreement with the reported standard bond distance [16].

The whole structure generally showed planar configuration. However, torsion angles such as N3/C5/C6/C1 (9°), C1/S1/C13/C14 (170.48°) and C13/C14/C15/C20 (5.26°) showed twisting between the consisting moieties.

The structure stabilized by hydrogen bonding (Figure 2a) between the nitrogen atoms and O21, as follows: N4–H4…O21, O21–H21A…N3 and O21–H21B…N1 according to the numbering in Figure 1. The packing showed parallel layers (Figure 2b).

Figure 2. (a): A segment of the structure showing hydrogen bonding as blue dotted lines. (b): Crystal packing.

3. Materials and Methods

3.1. General

Chemicals and solvents were obtained from Merck. The NMR spectra (500 MHz for ¹H and 125 MHz for ¹³C) of 4 were performed on a JEOLNMR spectrometer. The chemical shift (δ) was reported in ppm and the coupling constant (J) was measured in Hz. The NMR spectra were recorded in DMSO-d₆. Literature procedures were used to prepare 1 [17].

3.2. Synthesis of 4

A mixture of 1 (0.43 g, 2.0 mmol), potassium hydroxide (0.22 g, 4.0 mmol) and EtOH 80% (15 mL) was stirred in an ice bath for 15 min. Then, carbon disulfide (5 mL) was added and stirring was continued for 4 h. The solvent was evaporated, then the formed solid placed into a round bottom flask (50 mL) compound 3 (0.4 g, 2 mmol) and (15 mL) ethanol-water (1:1) were added. The new mixture was heated under reflux conditions for 3 h. The colorless solid produced was collected by filtration. The product was washed with EtOH, dried, and recrystallized from DMF to give 4 in a 76% yield; mp 134–135 °C. ¹H NMR: 2.49 (s, 3H, Me), 5.11 (s, 2H, CH₂), 7.45–8.04 (m, 10H, Ar), 12.97 (s, exch., 1H, NH). ¹³C NMR: 11.2, 40.1, 125.5, 127.5, 128.7, 129.0, 129.2, 129.3, 129.4, 133.1, 134.4, 134.5, 135.6, 146.2, 161.6, 193.2. Anal. Calcd. for C₂₀H₁₆N₄O₂S (376.43): C, 63.81; H, 4.28; N, 14.88. Found: C, 63.93; H, 4.39; N, 14.97%.

3.3. Crystal Structure Determination

A colorless crystal with approximate dimensions of 0.162 × 0.226 × 0.552 mm³ was placed and optically centered on a Bruker APEX-II CCD diffractometer (Mo-Kα radiations), the data collected through APEX 3 software package [18]. The structure was solved and refined using SHELXT [19] and SHELXL [20]. The crystallographic software packages PLATON [21], Mercury [22] and ORTEP-3 for Windows [23] were used for the analysis and graphical presentation of the structure.

The full crystallographic details are included in the Supplementary Materials (CIF and Tables S1–S4). The data have been deposited in the Cambridge Crystallographic Data Centre (CSD) with the number CCDC 2263548.

4. Conclusions

A new heterocycle containing imidazole and 1,3,4-oxadiazole moieties was synthesized with a good yield using a simple procedure. The structure of the title heterocycle was established using single-crystal X-ray diffraction and nuclear magnetic resonance spectroscopy.