MAOS versus conventional synthesis of 4,5-di-and 3,4,5-triphenylimidazole-2-thione and their derivatives

Microwave-Assisted Organic Synthesis (MAOS) of 4,5-di-and 3,4,5-triphenylimidazole ( 1 ) and ( 2 ) has been achieved by reaction of benzoin with ammonium thiocyanate and phenylthiourea, respectively. Reaction of 1 and 2 with chloroacetic acid and ethyl chloroacetate afforded the respective mercaptoacetic acid derivatives. Dehydrative cyclization of (4,5-diphenylimidazol-2-yl)mercaptoacetic acid ( 4 ) gave 5,6-diphenyl-2,3-dihydroimidazo[2,1-b ]thiazol-3-one ( 5 ) by action of acetic anhydride under MW irradiation. Hydrazinolysis of the thiazolone 5 , esters 6 and 7 gave 8 and 9 , respectively, whose condensation with aldehydes and isatin gave the respective hydrazones. MW irradiation led to higher yields in much less time than conventional methods. Selectivity and/or reactivity encountered during the reactions have been theoretically investigated by using the AM1 method for calculating the relative stabilities, charge densities, dipole moments and electronic energies of reactants and their tautomers.


Introduction
Microwave (MW) energy is well known to induce reduction in time of various reactions, yield enhancement and cleaner chemistry.Recently, this energy has been widely used as an alternative to conventional heating to a number of research programs and development processes, 1 whereby microwave-assisted organic synthesis (MAOS) become a fashion in organic chemistry.3][4][5] Substituted 2-thioimidazoles are present in compounds that have antiasthmatic, 6 antiinflammatory, 7 antiulcerative, 8 antithrombotic, 9 fungicidal 10 and herbicidal 11 activities.As resulting from the hindered rotation of azomethine linkage.This explanation has been deduced from the absence of such pairing in hydrazides 8 and 9.This isomerism may cause a difference in hydrogen bonding with DMSO-d 6 .However, for similar analogues such pairing was explained by the presence of hydrogen bonding between amide N-H and S atom. 18he imidazole ring was found to exist in thione-thiol equilibrium due to the mobility of the NH proton where the C-2 flanked between the two nitrogen atoms and can be linked to a mercapto or thione group (Scheme 1). 22Theoretical studies on the tautomerism in unsubstituted 2-mercaptoimidazole using the three semiemperical calculation methods (AM1, MNDO and PM3) has shown that the thiol form was more stable than the thione form. 23We have attempted to study theoretical approach to predict the tautomerism in di-and triphenyl-2mercaptoimidazoles 1 and 2 and its effect on regioselectivity of alkylation.This was performed by considering the theoretical calculations for 1 and 2 by means of semiemperical AM1 methods which were carried out with MOPAC7 program package. 24The heat of formation, dipole moment, highest occupied molecular orbital energies E HOMO , lowest unoccupied molecular orbital energies E LUMO and the charge density on imidazole heteroatoms as well as the relative stability of the tautomers of 1-3 have been taken into account (Table 1 The relative stability (RS) calculations from gas phase AM1 method for the diphenylimidazole favored the predominance of the thione form 1a over the thiol form 1b with relative stability energy (-0.629Kcal.mol -1 ).In contrast, the thiol form 2b in triphenylimidazole has been found to be more stable over the thione form 2a with relative stability energy (0.152 Kcal.mol -1 ) (Table 1).However, the value of RS for 2 is less than that of 1.
The predominance of the thiol form in compound 2 can be due to the electron withdrawing effect of the phenyl group on N-3, which has affected the charge density distribution on imidazole heteroatoms; the electron density was found to be shifted towards the nitrogen atom bearing the phenyl group, and hence stabilizes the thiol form.Further evidence of the effect of substituents on thiol-thione tautomerism was obtained by the study of N-methyl-4,5-phenyl-2mercaptoimidazole 3, where the thione form was found to be more predominant than thiol form with relative stability RS (-16.187Kcal.mol -1 ) (Table 1).
On the other hand, the charge density on imidazole heteroatoms (Table 1) has been mainly localized on the sulfur atom.These results explain the higher reactivity of the sulfur atom towards the electrophilic attack than nitrogen atoms, presumably due to the gain of higher nucleophilic properties and lower electronegativity of the sulfur atom. 22Accordingly the theoretical calculations agreed with the experimental results and the alkylation of 1 or 2 with ethyl chloroacetate in the presence of triethylamine as a basic catalyst has been directed the carboxymethylation to the S atom.

Conclusions
The synthesis of thioimidazole derivatives was successfully carried out by applying an environmental friendly and time saving protocol.
The AM1 semiemperical study were in agreement with the experimental data where the thione form in 4,5-diphenylimidazole-2-thione 1a was found to be the predominant form, while the thiol form 2b was the predominant one.

Experimental Section
General Procedures.Melting points were determined with a Melt-Temp apparatus and are uncorrected.TLC was performed on Baker-Flex silica gel using ethyl acetate-hexane as developing solvents, and the spot were detected by UV light absorption.Irradiation was done in a domestic microwave oven EM-230M (800 watt output power).IR spectra were recorded with Perkin-Elmer 1430 spectrometer. 1H NMR spectra were recorded on Jeol spectrometer (500 MHz).Chemical shifts δ are given in ppm relative to the signal for TMS as internal standard.The elemental analyses were performed by the microanalysis unit in the Faculty of Science, Cairo University.

3,4,5-Triphenylimidazole-2-thiol (2). Method A.
A mixture of benzoin (2.5 mmol) and phenylthiourea (5 mmol) was fused at 165-175 °C for 1h, then allowed to cool and treated with water (10 ml).The solid was filtered and recrystallized from ethanol, to give pale yellow crystals.mp 309-310 °C.Method B. A mixture of benzoin (2.5 mmol) and phenylthiourea (5 mmol) was irradiated by MW for 4 min, then allowed to cool and treated with water (10 ml).The solid was filtered and recrystallized from ethanol, to give

Table 2 .
Comparative data of conventional and MW methods for the synthesis of compounds 1-16