Convenient and regiospecific method for synthesis of 4,5-diaryl-1-methyl-2- (methylthio)-1H-imidazole

Article abstract of DOI:10.1080/00397911.2012.717670

A convenient, high-yielding, regiospecific synthesis of 1H-imidazole-2-thiones ring has been developed. In addition, a series of 4,5-diaryl-1-methyl-2-(methylthio)-1H-imidazoles 8 were synthesized and characterized. The structure of regioisomers was confirmed through nuclear Overhauser effect spectroscopy and NMR spectroscopy. Copyright

Full text of DOI:10.1080/00397911.2012.717670

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Convenient and Regiospecific Method
for Synthesis of 4,5-Diaryl-1-methyl-2-
(methylthio)-1H-imidazole
Amir Assadieskandar a , Marjan Salehi a , Mohsen Vosooghi a , Abbas
Shafiee b & Mohsen Amini a
a Department of Medicinal Chemistry, Faculty of Pharmacy and
Drug Design & Development Research Center , Tehran University of
Medical Sciences , Tehran , Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center , Tehran University of
Medical Sciences , Tehran , Iran
Accepted author version posted online: 26 Mar 2013.Published
online: 03 Jun 2013.
To cite this article: Amir Assadieskandar , Marjan Salehi , Mohsen Vosooghi , Abbas Shafiee
& Mohsen Amini (2013): Convenient and Regiospecific Method for Synthesis of 4,5-Diaryl-1-
methyl-2-(methylthio)-1H-imidazole, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:18, 2501-2507
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Synthetic Communications1, 43: 2501–2507, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.717670
CONVENIENT AND REGIOSPECIFIC METHOD FOR
SYNTHESIS OF 4,5-DIARYL-1-METHYL-
2-(METHYLTHIO)-1H-IMIDAZOLE
Amir Assadieskandar,1 Marjan Salehi,1 Mohsen Vosooghi,1
Abbas Shafiee,2 and Mohsen Amini1
1Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design
& Development Research Center, Tehran University of Medical Sciences,
Tehran, Iran
2Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A convenient, high-yielding, regiospecific synthesis of 1H-imidazole-2-thiones ring
has been developed. In addition, a series of 4,5-diaryl-1-methyl-2-(methylthio)-1H-imida-
zoles 8 were synthesized and characterized. The structure of regioisomers was confirmed
through nuclear Overhauser effect spectroscopy and NMR spectroscopy.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords 1H-Imidazole-2-thione; NOESY; regiospecific synthesis
INTRODUCTION
Imidazoles and imidazole-2-thiones scaffold have been incorporated into a
wide variety of pharmacologically active compounds and drug candidates including
antifungal, antiulcerative cytotoxic, and anti-inflammatory activities. They include
compounds that are inhibitors of phosphodiesterase, cyclooxygenase, lipoxygenase,
acyl CoA:cholesterol acyltransferase, and tubulin polymerization.[1–6] In continu-
ation of our research on design and synthesis of the diarylheterocycle scaffold,[7–9]
Received June 21, 2012.
Address correspondence to Mohsen Amini, Department of Medicinal Chemistry, Faculty of
Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences,
Tehran 14176, Iran. E-mail: moamini@sina.tums.ac.ir
2501

2502
A. ASSADIESKANDAR ET AL.
we focused on the synthesis of regionspecific 4,5-diaryl-1H-imidazole-2-thiones deri-
vatives. Herein we report a fast, convenient, and high-yielding method to regiospe-
cifically synthesize of 4,5-diarly-N-methyl-imidazole-2-thione. Furthermore, the
structure of two different regioisomers and the position of methyl group in the pro-
duct were confirmed through nuclear Overhauser (NOESY) and NMR spectroscopy.
RESULTS AND DISCUSSION
Synthesis of a-bromodesoxybenzoins was carried out by reacting appropriate
phenyl acetic acid with various substituted aromatic hydrocarbons. Subsequently,
desoxybenzoins 1 were subjected to bromination using bromine in glacial acetic acid
to obtain a-bromodesoxybenzoins 2 according to previous reports[10,11] (Scheme 1).
For regiospecific preparation of 4,5-diaryl-1-methyl-2-methylthio-1H-imidaz-
ole derivatives, three different methods were considered. In method A, a suspension
of a-bromodesoxybenzoin 2f, N,S-dimethylisothiourea, and K2CO3 in dry CH3CN
were stirred at room temperature for 18 h. However, the expected compound 8f
was not obtaied.[12]
In method B, a-bromodesoxybenzoin 2f was refluxed with sodium methoxide
in methanol. Subsequently, the reaction was quenched with cold 10% hydrochloric
acid to obtain benzoin 3.[13] The 1H-imidazole-2-thione 4 was prepared by refluxing
benzoin 3 with excess ammonium thiocyanate in n-butanol. Finally, compound 5
was prepared by S-methylation of 1H-imidazole-2-thione 4 with methyl iodide in
methanol with excellent yield. The preferential methylation of the 1H-imidazole-2-
thiones at the sulfur atom was due to its greater nucleophilicity.[14] On the other
hand, N-methylation of imidazole ring using iodomethane in the presence of a base
was not successful and obtained products were not regiospecific.[12–15] Our efforts
with N-methylation of compound 5 using iodomethane confirm this observation.
Finally, treatment of compounds 5 with excess dimethylformamide–dimethyla-
cetate (DMF-DMA) in toluene under reflux condition afforded two different regioi-
1
somer (8f and 8f0) in a 38:62 molar ratio. In H NMR of compounds 8f and 8f0, the
NCH3 group was observed in 3.42 and 3.40 ppm, and the OCH3 group was observed
in 3.77 and 3.88 ppm respectively. The significantly different chemical shift of meth-
oxy group in two regioisomers 8f and 8f0 could be due to the presence of a methyl
substituent at either nitrogen in the imidazole ring. The regioisomeric structure of
Scheme 1. Reagents and conditions: (a) H3PO4, (CF3CO)2O, 25 ꢀC ; (b) Br2, glacial AcOH, rt.

4,5-DIARYL-1-METHYL-2-(METHYLTHIO)-1H-IMIDAZOLE
2503
8f and 8f0 were confirmed through NOESY spectroscopy. A correlation between
NCH3 group at 3.42 and H-2, H-6 protons of 4-chlorophenyl ring at 7.26 ppm estab-
lishes the regiochemistry of 8f and correlation between NCH3 group at 3.40 and H-2,
H-6 protons of methoxyphenyl ring at 7.22 ppm establishes the regiochemistry of 8f0
respectivly. This observation was supported by the results from two-dimensional
NMR experiments in a series of regioisomeric N-substituted pyridin-4-yl imidazole
derivatives,[15] and also the correlation of the NCH3 group and H-2 and H-6 protons
of 4-chlorophenyl in 4,5-diarylimidazole compounds were previously reported based
on a NOE experiment[16]
Furthermore, compound 8f, which was prepared from method C, showed the
same spectroscopic data with the one prepared from method B (Scheme 2).
In method C, a-bromodesoxybenzoins 2, methylamine hydrochloride, and pot-
assium carbonate were refluxed in methanol. After 0.5 h (as monitored by thin-layer
chromatography, TLC), starting material disappeared and was completely converted
to a-N-methyl-desoxybenzoin 6. The efforts for separation of compounds 6 were not
successful because of the instability of the compounds; therefore they were used
without further purification and converted to 1H-imidazole-2-thione 7 by refluxing
with excess ammonium thiocyanate in n-butanol. Finally, regioisomers 8 were pre-
pared by S-methylation of 1H-imidazole-2-thione 7 with methyl iodide in methanol
(Scheme 3, Table 1). The chemical shifts of the aromatic protons were assigned based
on comparing 1H NMR of different synthesized compounds 7 and 8a–f and NOESY
Scheme 2. Reagents and conditions: (a) K2CO3, CH3CN, rt.; (b) CH3ONa, CH3OH, reflux, 10% HCl; (c)
NH4SCN, n-butanol, reflux; (d) CH3I, CH3OH, reflux; (e) DMF-DMA, toluene, reflux.

2504
A. ASSADIESKANDAR ET AL.
Scheme 3. Reagents and conditions: (a) NH2CH3 ꢁ HCl, K2CO3, CH3OH, reflux; (b) NH4SCN, n-butanol,
reflux; (c) CH3I, CH3OH, reflux.
Table 1. Synthesis of 7a–f and 8a–f
Compound
R1
R2
R
Yield (%)
Mp (ꢀC)
7a
7b
7c
7d
7e
7f
H
F
SCH3
SCH3
SCH3
OCH3
OCH3
OCH3
SCH3
SCH3
SCH3
OCH3
OCH3
OCH3
H
H
72
75
74
75
76
75
82
84
82
85
84
84
220–223
249–252
255–258
203–206
243–246
227–230
112–115
96–99
Cl
H
F
H
H
H
Cl
H
F
H
8a
8b
8c
8d
8e
8f
CH3
CH3
CH3
CH3
CH3
CH3
Cl
H
F
135–138
94–95
91–93
Cl
112–114
spectroscopy of compounds 7d–f and 8e–f. For additional support, NOE experiment
was used to assign the aromatic chemical shifts. For compounds 8f and 8f0, the
irradiation of the NCH3 in 3.42 and 3.40 showed an enhancement of the phenyl
hydrogen atoms signals in 7.26 and 7.22 ppm respectively.
In conclusion, we have developed a simple and highly efficient regiospecific
synthesis of 1H-imidazole-2-thiones derivatives.
EXPERIMENTAL
Reaction of Compound 5 with Dimethylformamide-dimethylacetate
To a solution of compound 5 (2 mmol) in toluene (10 mL), 2 mL DMF-DMA
was added, and the reaction was refluxed for 24 h. The solvent evaporated under
reduced pressure and the residue was purified by preparative TLC on silica gel using
ethyl acetate–petroleum ether (1:2) as mobile phase.

4,5-DIARYL-1-METHYL-2-(METHYLTHIO)-1H-IMIDAZOLE
2505
4-(4-Chlorophenyl)-5-(4-methoxyphenyl)-1-methyl-2-(methylthio)-1H-
imidazole (8f’). Yield, 52%; mp 108–110 ꢀC; IR (KBr, cmꢂ1): v1512, 1246, 1170,
1
1076, 854; H NMR (CDCl3): d 2.70 (s, 3H, SCH3), 3.40 (s, 3H, NCH3), 3.88 (s,
3H, OCH3), 6.99 (d, J ¼ 8.5, 2H, methoxyphenyl H-3, H-5), 7.16 (d, J ¼ 8.5, 2H,
chlorophenyl H-2, H-6), 7.22 (d, J ¼ 8.5, 2H, methoxyphenyl H-2, H-6), 7.43 (d,
J ¼ 8.5, 2H, chlorophenyl H-3, H-5). 13C NMR (CDCl3): d 16.26, 31.40, 55.32,
114.61, 122.67, 127.70, 128.22, 130.68, 131.74, 131.89, 133.15, 136.99, 142.80,
159.95. Anal. calcd. for C18H17ClN2OS: C, 62.69; H, 4.97; N, 8.12. Found: C,
62.75; H, 4.76; N, 8.33.
5-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-methyl-2-(methylthio)-1H-
imidazole (8f). Yield, 25%; mp 112-114 ꢀC; IR (KBr, cmꢂ1): v 1510, 1250, 1172,
1
1087, 846; H NMR (CDCl3): d 2.71 (s, 3H, SCH3), 3.42 (s, 3H, NCH3), 3.78 (s,
3H, OCH3), 6.78 (d, J ¼ 8.5, 2H, methoxyphenyl H-3, H-5), 7.26 (d, J ¼ 8.5, 2H,
chlorophenyl H-2, H-6), 7.38 (d, J ¼ 8.5, 2H, methoxyphenyl H-2, H-6), 7.43 (d,
J ¼ 8.5, 2H, chlorophenyl H-3, H-5). 13C NMR (CDCl3): d 16.31, 31.56, 55.19,
113.65, 126.93, 128.03, 128.35, 129.32, 130.68, 129.52, 132.00, 134.50, 138.57,
143.15, 158.39. Anal. calcd. for C18H17ClN2OS: C, 62.69; H, 4.97; N, 8.12. Found:
C, 62.83; H, 4.76; N, 8.23.
General Procedure for Regiospecific Synthesis of Compounds 7
Methylamine hydrochloride (2 mmol) and potassium carbonate (4 mmol) were
added to a stirring solution of related a-bromodesoxybenzoin 2 (1 mmol) in meth-
anol (50 mL), and the mixture was refluxed for 0.5 h. The solvent was removed under
reduced pressure. Water (20 mL) and ehtylacetate (50 mL) were added to the residue.
The organic phase was separated, dried (sodium sulfate), filtered, and evaporated
under reduced pressure. The residue was disolved in n-butanol (50 mL), and 4 mmol
ammonium thiocyanate was added. The mixture refluxed for 0.5 h, and then 50 mL
water was added. The organic phase was separated, dried (sodium sulfate), filtered,
and evaporated under reduced pressure. The residue was crystallized in methanol.
General Procedure for S-Methylation of Compounds 8
Methyl iodide (1.5 mmol) and triethylamine (0.5 mL) were added to a stirring
solution of compound 7 (1 mmol) in methanol (50 mL), and the mixture was refluxed
for 2 h. The solvent was removed under reduced pressure. Water (20 mL) and ehty-
lacetate (50 mL) were added to the residue. The organic phase was separated, dried
(sodium sulfate), filtered, and evaporated under reduced pressure. The residue was
crystallized in petroleum ether.
SUPPLEMENTARY MATERIAL
1
Full experimental detail, H NMR, 13C NMR, and NOESY spectra can be
found via the Supplementary Content section of this article’s Web page.

2506
A. ASSADIESKANDAR ET AL.
ACKNOWLEDGMENT
This research has been supported by Tehran University of Medical Sciences &
Health Services grant no. 15098.
REFERENCES
1. Bellina, F.; Cauteruccio, S.; Rossi, R. Synthesis and biological activity of vicinal
diaryl-substituted 1H-imidazoles. Tetrahedron 2007, 63, 4571–4624.
2. Salimi, M.; Ghahremani, M. H.; Naderi, N.; Amini, M.; Salimi, E.; Amanlou, M.; Abdi, K.;
Salehi, R.; Shafiee, A. Design, synthesis, and pharmacological evaluation of 4-[2-alkylthio-
5(4)-(4-substitutedphenyl)imidazole-4(5)yl]benzenesulfonamides as selective COX-2 inhibi-
tors. Acta Pharmacol. Sin. 2007, 28, 1254–1260.
3. Sharpe, T. R.; Cherkofsky, S. C.; Hewes, W. E.; Smith, D. H.; Gregory, W. A.; Haber, S. B.;
Leadbetter, M. R.; Whitney, J. G. Preparation and antiarthritic and analgesic activity of
4,5-diaryl-2-(substituted thio)-1H-imidazoles and their sulfoxides and sulfones. J. Med.
Chem. 1985, 28, 1188–1194.
4. Higley, C. A.; Wilde, R. G.; Maduskuie, T. P.; Johnson, A. L.; Pennev, P.; Billheimer, J. T.;
Robinson, C. S.; Gillies, P. J.; Wexler, R. R. Acyl CoA:cholesterol acyltransferase (ACAT)
inhibitors: Synthesis and structure–activity relationship studies of a new series of trisubsti-
tuted imidazoles. J. Med. Chem. 1994, 37, 3511–3522.
5. Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht, W. Novel substituted
pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cyto-
chrome P450 enzymes. J. Med. Chem. 2003, 46, 3230–3244.
6. Schobert, R.; Biersack, B.; Dietrich, A.; Effenberger, K.; Knauer, S.; Mueller, T.
4-(3-Halo=amino-4,5-dimethoxyphenyl)-5-aryloxazoles and -N-methylimidazoles that
are cytotoxic against combretastatin A–resistant tumor cells and vascular disrupting in
a cisplatin-resistant germ cell tumor model. J. Med. Chem. 2010, 53, 6595–6602.
7. Assadieskandar, A.; Amini, M.; Haukka, M.; Shafiee, A. Reaction of 2-alkoxy-4,5-
diphenyl-1,3-oxazin-6-one with different alcohols and elucidation of the products. J. Hetero-
cycl. Chem. 2012, 49, 358–362.
8. Irannejad, H.; Amini, M.; Khodagholi, F.; Ansari, N.; Tusi, S. K.; Sharifzadeh, M.;
Shafiee, A. Synthesis and in vitro evaluation of novel 1,2,4-triazine derivatives as neuro-
protective agents. Bioorg. Med. Chem. 2010, 18, 4224–4230.
9. Salimi, M.; Amini, M.; Shafiee, A. Syntheses of 2-alkylthio-(4,5-diaryl)imidazoles.
Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 1587–1592.
10. Gadad, A. K.; Palkar, M. B.; Arland, K.; Noolvi, M. N.; Boreddy, T. S.; Wagwade, J.
Synthesis and biological evaluation of 2-trifluoromethyl=sulfonamido-5,6-diaryl substi-
tuted imidazo[2,1-b]-1,3,4-thiadiazoles: A novel class of cyclooxygenase-2 inhibitors.
2008, 16, 276–283.
11. Veeramaneni, V. R.; Pal, M.; Yeleswarapu, K. R. A high-speed parallel synthesis of
1,2-diaryl-1-ethanones via a clean-chemistry C-C bond formation reaction. Tetrahedron
2007, 59, 3283–3290.
12. Bender, P. E.; Hill, D. T.; Offen, P. H.; Razgaitis, K.; Lavanchy, P.; Stringer, O. D.;
Sutton, B. M.; Griswold, D. E.; DiMartino, M.; Walz, D. T.; et al. 5,6-Diaryl-2,3-
dihydroimidazo[2,1-b]thiazoles: A new class of immunoregulatory anti-inflammatory
agents. J. Med. Chem. 1985, 28, 1169–1177.
13. Nagano, T. Triphenylethylene derivatives III. J. Org. Chem. 1957, 22, 817–818.
14. Aouad, M. R.; Rezki, N.; El Ahsry, E. H. Regioselectivity of the reactions of
4,5-diphenylimidazole-2-thione with 1-chloro-2,3-epoxy-propane and 1-bromo-propene,

4,5-DIARYL-1-METHYL-2-(METHYLTHIO)-1H-IMIDAZOLE
2507
efficient precursors for imidazo[2,1-b]thiazine and thiazole: Effect of microwave and solid
support. J. Heterocycl. Chem. 2008, 45, 1321–1327.
15. Wagner, G. K.; Kotschenreuther, D.; Zimmermann, W.; Laufer, S. A. Identification of
regioisomers in a series of N-substituted pyridin-4-yl imidazole derivatives by regiospecific
synthesis, GC=MS, and H-1 NMR. J. Org. Chem. 2003, 68, 4527–4530.
16. Plummer, C. W.; Finke, P. E.; Mills, S. G.; Wang, J. Y.; Tong, X. C.; Doss, G. A.; Fong, T. M.;
Lao, J. Z.; Schaeffer, M. T.; Chen, J.; Shen, C. P.; Stribling, D. S.; Shearman, L. P.; Strack, A.
M.; Van der Ploeg, L. H. T. Synthesis and activity of 4,5-diarylimidazoles as human CB1
receptor inverse agonists. Bioorg. Med. Chem. Lett. 2005, 15, 1441–1446.