الفهرس 
Introduction
Five-membered Rings with One HeteroatomOnly 14 pages are availabe for public view
 |  | from | 156 |  |  |
| | | from | 156 | | |
Abstract
As a part of an ongoing program aiming at the synthesis of bis-heterocyclic compounds, we report here the versatile and hitherto unreported, synthesis of 5,5`-(1,4-phenylenebis-(methanylylidene))bis-thiohydantoins and screened their antimicrobial activities.
(Part 1): Synthesis and Antimicrobial Activities
The synthesis of (5-Z,5`Z)-5,5`-(1,4-phenylenebis-(methanylylidene))-bis(3-substituted-2-thioxoimidazolidin-4-one) derivatives 186a-d by three different methods (A-C) is outlined in Scheme 1. The method (A) involves one-put , three-component condensation of terephthalaldehyde (1), glycine (184) and substituted isothiocyanates 185a-d in a molar ratio 1:2:2 in refluxing glacial acetic acid .
To chemically verify the structure of bis-thiohydantoins 186a-d they were prepared through a two-component condensation of terephthalaldehyde (1) with 2-thiohydantoin 187a-c in a molar ratio 1:2 in refluxing acetic acid and in the presence of anhydrous sodium acetate (method B).
Additionally, the method C is based on the two-step one-pot synthesis utilizing the same starting materials mentioned above in method B.In the first step, terephthalaldehyde (1) reacts with 2 equivalents of 187a-c in the presence of potassium hydroxide in anhydrous ethanol. In the second step, the potassium salt of 4,4`-(1,4-phenylenebis(methanylylidene))bis(5-oxo-1-phenyl-4,5-dihydro-1H-imidazole-2-thiolate) is hydrolyzed with dilute hydrochloric acid.
The molecular structures of the bis-thiohydantoins 186a-d were confirmed by their elemental analyses and spectral data (IR, 1H NMR, 13C NMR, and MS), which were found to be in agreement with the assigned structures (Figs. 1-16).
The spectral data of compound 186a-d indicated that they exist in the thioamide-form 186a: IR spectra showed no absorption of the SH group, but band due to the N-C=S group is observed. The tautomeric equilibrium between thioamide-form 186a and iminothiol-form186a\ seems to be widely shifted toward the thioamide-form 186a .
All the bis-thiohydantoins 186a-d were isolated as single geometric isomer, which were identified as the Z-isomers basing on the chemical shifts of the vinyl protons in the region of δ: 6.74-6.93 in the 1H NMR spectra and signals of the vinyl carbons in the region of δ :111.37-112.35 in the 13C NMR spectra.
The bis-thiohydantoins 186a was subjected to alkylation with iodomethane in ethanolic potassium hydroxide at room temperature to afford the corresponding S-methylated derivative 188a (Scheme 2). Meanwhile, the reaction of 186a with benzyl chloride in DMF
in the presence of anhydrous potassium carbonate at room temperature gave the S-benzylated derivative 188b (Scheme 2).
The structures of 188a and 188b were deduced from their elemental analyses and their spectral data(IR , 1H , 13C NMR and MS)(Figs. 17-24). Compounds 188a and 188b were isolated as single geometric isomer, as shown by the presence of only one set of signals in each of 1H and 13C NMR, which were identified as the Z-isomer.
The protocol was extended for the synthesis of (5-E,5`E)-5,5`-(1,4-phenylene-bis(methanylylidene))bis(1-methyl-3-substituted-2-thioxo-imidazolidin-4-one) derivatives 190a-d by using two different methods. Method A relies on the one-pot three-component condensation reaction of terephthalaldehyde (1), isothiocyanates 185a-d and sarcosine (189) in a molar ratio 1:2:2 in refluxing ethanol containing triethylamine (Scheme 3).
Alternatively, compound 190a could also be prepared by the Knoevenagel condensation reaction of terephthalaldehyde (1) with 1-methyl-3-phenyl-2-thiohydantoin (191) in a molar ratio 1:2 in refluxing ethanol containing a catalytic amount of morpholine (method B, Scheme 3). The structures of 190a-d were deduced from their elemental analyses and their spectral data(IR , 1H , 13C NMR and MS) (Fig. 25-40).
The literature survey, indicated that the condensation of aromatic aldehydes with 1-methyl-hydantoin afforded a mixture of both possible geometric isomers 5-(Z)- and 5-(E)-arylidene1-methyl-hydantoins. In our experiments, all the bis-thiohydantoins 190a-d were isolated as single geometric isomer, which was identified as the E-isomer based on 1H and 13C NMR spectral data. Thus, the 13C NMR spectra of 190a-d showed the presence of a signals at δ: 119.19-120.69 ppm assigned to the vinyl carbon, likewise indicating the presence of an E-configuration for the exocyclic double bond, in agreement with the 13C NMR spectra of 5-(Z)- and 5-(E)-arylidenehydantoin derivatives whose vinyl groups appear at δ: 105-115 and 115-125 ppm, respectively.
Some of the prepared compounds were screened for their in vitro antimicrobial activity . The results of antibacterial screening have been revealed that the tested compounds 186a, 188b, 190b and 190c had low effect against gram positive bacteria Bacillus cereus. The antifungal screening revealed that most of the tested compounds showed good, moderate to low fungal inhibition. Compound 186b was the most effective compound against Fusarium oxysporum, while other compounds showed moderate (190a and 190c) to low activity (186a, 188a, 188b, and 190b).
(Part 2): Conformational search and energy calculations
The current study was performed to introduce a theoretical investigation for (E/Z) geometrical isomers of the bis-arylidene-2-thiohydantoin derivatives. In order to obtain the most stable structure for E/Z isomers, a large number of conformers must be generated, minimized and compared to each other according to their energies. This generation called conformational search which could be performed using molecular mechanical calculations with the help of an appropriate force filed. Conformational search for 186a, 188a and 190a derivatives was performed using OMEGA software. The responsible positions for (E/Z) geometrical isomers of 186a, 188a and 190a derivatives are illustrated in Fig. 41. The conformers from each group of E/Z conformers were optimized using B3LYP/6-31+G* level of theory. Single point energy calculations were performed using density functional theory (DFT) and Møller–Plesset perturbation theory (MP2). The 6-31+G* and aug-cc-PVDZ basis sets were used for B3LYP and MP2, respectively. The most stable conformers were investigated for the three studied derivatives.
Fig. (41): Systematic representation for the two positions of (Z/E)-configurations. Position I and II refer to the Z- and E-configuration.