Morpholinium hydrogen sulfate (MHS) ionic liquid as an efficient catalyst for the synthesis of bio-active multi-substituted imidazoles (MSI) under solvent-free conditions

2.1 Molecular structures of 5a and 5c

The molecular structures of 5a and 5c were determination by single-crystal X-ray diffraction (Fig. 1; and Experimental section). Table 4 summarizes characteristic dihedral angles between the imidazole and benzene rings of 5a and 5c.

Fig. 1:

The molecular structures of (a) 5a and (b) 5c in the crystal with the crystallographic atom numbering scheme adopted. Displacement ellipsoids are drawn at the 50% probability level. For clarity only the major disorder component of the disordered 2-hydroxypropyl substituent of 5c is shown.

2.2 Anti-inflammatory activity

The effect of the 10 new imidazoles reported here as anti-inflammatory agents was studied using the sulfated polysaccharide carrageenan and applying the standard carrageenan-induced paw edema method in rats. The method was applied to both male and female albino rats with weights in the range 160–190 g. The animals (pregnant female animals were excluded) were housed in cages made of stainless steel and divided into 15 groups each of six animals. Before the experiment, animals were fasted by depriving them of food but not water for 24 h (each rat was given 3 mL of water orally) to minimize the variability of the edema response. The imidazole compounds under investigation (10 mg kg⁻¹ body weight) and indomethacin (as a reference standard) were suspended in saline solution using a small amount of Tween 80 as a surfactant to enhance wettability of the drug particles. Test and control groups were then given the saline solution orally 1 h before induction of inflammation.

Carrageenan paw edema was produced according to a modified method of Winter et al. [29]. After 1 h, 0.1 mL of freshly prepared 1% carrageenan solution in normal saline was injected subcutaneously into the subplantar region of the right hind paw of the rat (0.1 mL per rat). The rat’s right paw thickness was checked with a mercury electronic digital micrometer (LDM-150) at different time intervals, at zero time and 1, 2, 3, 4, and 5 h after carrageenan induction. The edema was confirmed by observing the difference in thickness between injected and non-injected paws.

All data were calculated and analyzed quantitatively. Variables from normal distribution were referred to as means±standard error. The significant difference between groups was calculated by applying a one-way analysis of variance test followed by a post hoc test at P<0.05 and P<0.01.

The results were expressed as percentage of edema inhibition (OI, %) indicating the anti-inflammatory action. In other words, thickness in treated animals was compared with that in the control group and calculated using the following equation [30] (Table 5).

OI  (%)=(VR−VL)C−(VR−VL)T(VR−VL)C × 100

where V_R is the mean thickness of the right paw, V_L is the mean thickness of the left paw, (V_R – V_L)_C is the mean increase in the thickness of the paws in the control group of rats, and (V_R – V_L)_T is the mean increase in the thickness of the paws in rats treated with the compounds under investigation [31].

2.3 Anti-inflammatory results

The anti-inflammatory activity of the 10 synthesized compounds was estimated by monitoring carrageenan-induced paw edema in rats [32]. Generally, it has been observed (Table 5) that all of the compounds investigated exhibit considerable anti-inflammatory activity. In particular, however, compound 5h showed excellent anti-inflammatory properties (65.0% OI), somewhat better than the standard indomethacin (64.5% OI).

Comparing the activity of compounds 5d, 5e, 5f, and 5h that vary only by the nature of the substituents on the benzene ring at the 2-position of the imidazole ring reveals that a compound with a strong electron-donating substituent group, 4-N(CH₃)₂, as in 5h showed higher anti-inflammatory activity in comparison to those with electron-withdrawing substituents such as 4-COOH, 4-Cl, and 4-Br.

4.1 General

All chemical reagents and instruments were bought from Aldrich or Merck and used directly without further purification. Our products were characterized from spectroscopic data (FTIR, ¹H and ¹³C NMR, and mass spectra) and melting points. A SHIMADZU FT-IR-8400s spectrometer was used to record IR spectra using KBr pellets. NMR spectra were recorded on a Bruker (400 MHz) Ultrashield NMR spectrometer with [D₆]DMSO as a solvent. The purity of the substances and progress of the reactions were monitored by thin-layer chromatography (TLC) and melting points recorded by the open capillary method using a Gallenkamp melting point apparatus and are uncorrected.

4.2 Synthesis of the catalytic ionic liquid MHS

Morpholine (20 mmol) was added to a 150-mL three-necked flask with a magnetic stirrer. Then an equimolar quantity of sulfuric acid (concentrated) was slowly added dropwise to the flask in an ice bath. The reaction mixture was then stirred at 80°C for overnight, washed with diethyl ether several times to separate out the non-ionic residues, and dried under vacuum using a rotary evaporator to yield MHS as a clear viscous liquid.

4.3 General procedure for the synthesis of 1,2,4,5-tetrasubstituted imidazoles (5a–5j) using MHS as an ionic liquid catalyst

Benzil (10 mmol), an aldehyde (2a–j) (10 mmol), ammonium acetate (10 mmol), and 1-amino-2-propanol (10 mmol) were added to MHS (4 mmol) in an oil bath at 25°C. The resulting mixture was refluxed at 100°C for the time reported in Table 1. The reaction progress was monitored by TLC until completion. The reaction mixtures were next washed with distilled water, and the resulting solid products purified in all cases by recrystallization from absolute ethanol.

4.4 X-ray structure determinations of 5a and 5c

Crystallographic data for 5a and 5c are listed in Table 6. The diffraction data were obtained on an Agilent SuperNova, Dual, Cu at zero, Atlas diffractometer using a mirror monochromator and CuK_α radiation (λ=1.5418 Å). The data collection, cell refinement, data reduction, and absorption corrections were applied using Crysalis Pro [33]. The structures were both solved with Shelxs [34] and refined by full-matrix least squares on F² using Shelxl-2014 [35] and Titan2000 [36]. All non-hydrogen atoms were assigned anisotropic displacement parameters. The H atoms of the hydroxyl groups of both molecules were located in difference Fourier maps and their coordinates refined with atomic displacement parameters set to 1.5 U_eq(O). All other H atoms were positioned geometrically and refined using a riding model with d(C–H)=0.95 Å for aromatic and 0.99 Å for CH₂ with U_iso=1.2U_eq(C) and 0.98 Å, U_iso=1.5U_eq(C), for CH₃ atoms. Although 5a and 5c both crystallized in non-centrosymmetric space groups, P2₁2₁2₁ and P2₁, respectively, the absence of heavy atoms from the structures meant that the absolute configurations could not be determined from anomalous scattering effects. For 5c high and increasing atomic displacement parameters for the C12 and C13 atoms suggested disorder and these were split over to two positions with an occupancy ratio that converged at 0.525(19):0.475(19). All molecular plots and packing diagrams were drawn using Mercury [37]. Other calculations were performed using Platon [38] and tabular material was produced using WinGX [39].

CCDC 1479433 and CCDC 1479434 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.