Synthesis of 2-(methylsulfonyl)-5-(4-(methylsulfonyl) phenyl)-4-phenyl-1H-[5-14C]imidazole, a selective COX-2 inhibitor, via asymmetrical benzoins

Full text of DOI:10.1002/jlcr.3382

Research article
Received 21 November 2015,
Revised 22 December 2015,
Accepted 29 January 2016
Published online 24 February 2016 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3382
Synthesis of 2-(methylsulfonyl)-5-(4-
14
(methylsulfonyl) phenyl)-4-phenyl-1H-[5- C]
imidazole, a selective COX-2 inhibitor, via
asymmetrical benzoins
a
b
c
*
Gholamhossein Shirvani, Abbas Shockravi, Mohsen Amini, and
Nader Saemiana§
4,5-Diarylimidazoles labeled with carbon-14 in the 5-position of the imidazole ring were prepared as a part of three-step
sequence from 2-hydroxy-1-(4-(methylthio)phenyl)-2-phenyl[1-14C]ethanone as a key synthetic intermediate which has been
synthesized from potassium [14C]cyanide.
Keywords: 4,5-diarylimidazole; asymmetrical benzoins; selective COX-2 inhibitors; carbon-14
central rings in this class of molecules which exemplified by
Introduction
celecoxib (Celebrex).17–19
Extensive studies have been conducted on selective cyclo-
The design and synthesis of new cyclooxygenase inhibitors
are currently under investigation in order to find safer lead
compounds. Unfortunately, these compounds are associated
with adverse cardiovascular effects such as myocardial infarction,
oxygenase (COX-2) inhibitors in the past 10 years.1–8 COX
inhibitors can reduce pain and inflammatory markers. Aspirin,
indomethacin, celecoxib and many other COX inhibitors have
been extensively used as anti-inflammation drugs.9 COX-1 and
thrombosis and cardiac dysfunction. The most plausible reason
COX-2 are two types of COX enzymes differing only in the amino
for this effect is the suppression of COX-2 dependent prosta-
cyclin which mediates platelet activation and atherogenesis.11
acid at position 523. In COX-2, valine has been identified as
523rd amino acid that was substituted by isoleucine in the
COX-1 structure. Therefore, the smaller size of valine 523 allows
access to the hydrophobic pocket easily for COX-2 selective
Therefore, the search for a novel, structurally different and
better pharmacodynamic profile of selective COX-2 inhibitors
devoid of the noted side effects is still an ongoing need for
anti-inflammatory therapy. Some diaryl-heterocycles bearing a
compounds. Selective COX-2 inhibitors such as celecoxib could
be designed based on the consideration of the different active
6-alkylthio substituted lactone (pyrane-2-one) in the central
sites of the two subtypes of the COX enzymes.10 Gastrointestinal
ring have been reported to possess good selectivity toward
COX-215. 3-Alkylthio-4,5-diaryl-1,2,4-triazole14 and some 2-alkylthio
side effects were recognized as major side effect of traditional
substituted 1,5-diaryl-imidazole analogs13 also represent good
non-steroidal anti-inflammatory drugs such as aspirin, indometh-
acin, diclofenac and many others that have been categorized
as non-selective COX inhibitors (NSAIDs). This important side
effect limits the long usage of NSAIDs in chronic inflammation
disease.9
COX-2 selectivity and anti-inflammatory effects.
aNuclear Science Research School, Nuclear Science and Technology Research
Institute, End of North Karegar Ave 14395-836 Tehran, Iran
The overall host–guest interactions of selective inhibitors such
as 4,5-diarylimidazoles consist of hydrogen bond formation and
van der waals forces.11 These stereoelectronic interactions can
be affected by electron-withdrawing and electron-donating
groups.12 A common base structural motif of the most COX-2
selective inhibitors consists of two aryl groups linked to ad-
joining atoms of a central ring, which can be homocyclic or
heterocyclic.13–16 One of the aryl groups is substituted in the para
position with an aminosulfonyl (SO2NH2) or a methylsulfonyl
(SO2CH3) group. There are also examples of potent COX-2
inhibitors that possess cycloalkyl, alkoxy or phenoxy moieties in
the non-sulfonyl containing ‘aryl’ region. Thiophene, pyrazole,
furanone, isoxazole and cyclopentene are commonly used as
bFaculty of Chemistry, Kharazmi University (formerly Tarbiat Moallem University),
49 Mofetteh Avenue 15719-14911 Tehran, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy and Drug Design
Development Research Center, Tehran University of Medical Sciences, Tehran
14176, Iran
*Correspondence to: Abbas Shockravi, Faculty of Chemistry, Kharazmi University
(formerly Tarbiat Moallem University), 49 Mofetteh Avenue, 15719-14911 Tehran,
Iran.
E-mail: abbas_shockravi@yahoo.co.uk
§ This paper is dedicated to memory of Dr. Nader Saemian.
J. Label Compd. Radiopharm 2016, 59 153–156
Copyright © 2016 John Wiley & Sons, Ltd.

G. Shirvani et al.
Some 4,5-diaryl-imidazoles bearing a sulfonyl methyl phar- hydroxy-1-(4-(methylthio)phenyl)-2-phenyl[1-14C]ethanone 1 was
macophore on one of the adjacent phenyl rings and also produced via the reaction between 9 and sodium methoxide
containing a 2-alkylthio or 2-sulfonylalkyl on the imidazole ring in methanol.21,41–45 Conversion of 1 to 4-(4-(methylthio)phenyl)-
were synthesized with the aim of investigating the effect of 5-phenyl-1,3-dihydro-2H-[4-14C]imidazole-2-thione 10 was accom-
these groups on COX selectivity and potency.20–22
plished in the presence of excess ammonium thiocyanate in
To further clarify the mechanism of action and to augment the n-butanol as a solvent.22 2-(Methylthio)-5-(4-(methylthio)phenyl)-
on-going inhibitor studies, there is growing need to synthesize 4-phenyl-1H-[5-14C]imidazole 11 was produced via the reaction
the corresponding carbon-14 compounds with the label situated between 10 and methyl iodide in the presence of
in a biologically stable site. In this paper we present a convenient triethylamine and methanol under refluxing conditions. The
synthetic pathway for the synthesis of a series of 2-alkylthio or last compound, 2-(methylsulfonyl)-5-(4-(methylsulfonyl)phenyl)-
2-sulfonylalkyl substituted aromatics on the imidazole ring 4-phenyl-1H-[5-14C]imidazole 12, was synthesized by oxidation
labeled with carbon-14 via 2-hydroxy-1-(4-(methylthio)phenyl)- of 11 with oxone in methanol and THF at 0 °C.15
2-phenyl[1-14C]ethanone 1 as a key synthetic intermediate which
has been synthesized as part of a 4-step sequence from barium
Experimental
[14C]carbonate (Figure 1).
Barium [14C]carbonate (235.9 MBq/mmol) was converted to potassium
[
14C]cyanide according to the standard procedure.23 1H-NMR spectra
Result and discussion
were recorded on Bruker AVANCE 500 spectrometer. The IR spectra were
taken using Nicolet FT-IR Magna 550 spectrographs (KBr disks).
The route to [14C] 12 is shown in scheme 1. Barium [14C]carbonate
2 was converted to potassium [14C]cyanide 3 under standard
conditions. Benzyl [cyano-14C] cyanide 5 was derived from
reaction of benzyl chloride 4 and potassium [14C]cyanide 3 in
dry acetone and sodium iodide in good yield.24–26 The product
5 was hydrolyzed under acidic conditions to 2-phenyl[1-14C]
acetic acid 6.27–30 By reaction between methyl phenyl sulfide 7
and 6 in the presence of phosphoric acid and trifluoroacetic
anhydride produced compound 1-(4-(methylthio)phenyl)-2-
phenyl[1-14C]ethanone 8.20,21,31–33 Compound 8 was treated with
2-Phenyl[1-14C]acetic acid 6
In a 10-mL round-bottomed flask, fitted with a reflux condenser
capped by a drying tube, were placed dried benzyl chloride (1 g,
7.94 mmol), potassium
sodium iodide (74.4 mg) and dry acetone (4 mL). The mixture was
heated at reflux temperature for 20 h. After cooling to room tem-
perature, the reaction mixture was filtered and the filter cake washed
with acetone. Then the filtered mixture was evaporated, and oily
[
14C]cyanide (318 MBq, 228 mg, 3.4 mmol),
bromine in acetic acid as solvent to give 2-bromo-1-(4- residue was dissolved in 50-mL ethyl acetate and the later solution
(methylthio)phenyl)-2-phenyl[1-14C]ethanone 9.34–40 Then 2-
was washed twice with 30 mL water. The solution was dried over
anhydrous sodium sulfate and dried in vacuo. The crude benzyl
cyanide, which was prepared from last step, was added to a solution
of concentrated sulfuric acid (0.3 mL), glacial acetic acid (0.3 mL) and
H2O (0.3 mL). The mixture was refluxed for 45 min, then water was
added to the mixture. Ethyl acetate was added to the mixture and
the organic layer was separated, dried over sodium sulfate and the
residue was purified by silica gel chromatography using ethyl acetate:
hexane (50%) as eluent to give the title compound 6 (199 mg,
135 MBq) in 42% radiochemical yield. 1H-NMR (CDCl3, TMS) δ(ppm):
7.23–7.38 (m, 5H, ArH); 3.64 (s, 2H).
Figure 1. The key synthetic intermediate 1 for 14C-labeling of adjacent aryl groups
on imidazole ring.
Scheme 1. a) According to the standard procedure23; b) NaI, acetone; c) H2SO4, reflux; d) H3PO4, (CF3CO)2O, 25 °C; e) Br2, acetic acid; f) CH3ONa, CH3OH, reflux; g) NH4SCN,
n-Butanol, reflux; h) CH3I, Et3N, CH3OH, reflux; i) Oxone (potassium peroxymonosulfate), CH3OH/THF/H2O, 0 °C.
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Copyright © 2016 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2016, 59 153–156

G. Shirvani et al.
1-(4-(Methylthio)phenyl)-2-phenyl[1-14C]ethanone 8
Trifluoroacetic anhydride (5.62 mmol, 0.8 mL) was added to the mixture
of phenyl acetic acid (192 mg, 130 MBq), methyl phenyl sulfide
(1.68 mmol, 0.2 mL) and orthophosphoric acid (1.68 mmol, 0.8 mL)
rapidly with vigorous stirring at room temperature, and the mixture
was stirred for one extra minute and poured into 10-mL ice-cold water
with stirring. Then it was washed with cold hexane(2 × 2 mL) to obtain
title compound 8 as solid. The radiochemical yield (204 mg, 78 MBq)
was 60%. 1H NMR (CDCl3) δ(ppm): 7.84(d, J = 9 Hz, 2H,ArH),7.274–
7.150(m, 7H, ArH), 4.164 (s, 2H, CH2), 2.434 (s, 3H, SCH3).
2-Bromo-1-(4-(methylthio)phenyl)-2-phenyl[1-14C]ethanone 9
1-(4-(Methylthio)phenyl)-2-phenyl[1-14C]ethanone 8 (157 mg, 60 MBq)
and unlabeled 8 (553 mg) were mixed carefully and added to acetic acid
(3.31 mL) in a round bottom flask fitted with a reflux condenser. Bromine
(0.13 mL) was added to acetic acid (1.1 mL), and this solution was added
gradually to flask within 1 h. The mixture was stirred at room temperature
for 24 h, and the title compound was purified by silica gel column
chromatography and ethyl acetate: n-hexane (20:80) as eluent.
Radiochemical yield (750 mg, 48 MBq) was 80% (20.6 MBq/mmol);
1HNMR (CDCl3) δ(ppm): 7.833–7.816 (two, dd, 2H, J1 = 8Hz, J2 = 1Hz,
ArH); 7.458–7.442 (two, dd, 2H, J1 = 8Hz, J2 = 1Hz, ArH); 7.319–7.149
(m, 5H, ArH); 6.265 (s, 1H, CHBr); 2.432 (s, 3H, SCH3).
Scheme 2. Convenient synthetic pathway for labeling of
diarylimidazole with carbon-14.
a series of 4,5-
acetate. Further purification was carried out by silica gel column
chromatography using ethyl acetate:hexane (80:20) as eluent. The
radiochemical yield of title compound 12 was 89% (65 mg, 3.56 MBq),
and the overall radiochemical yield from K14CN was 6.3%. 1HNMR
(CDCl3) δ(ppm): 3.095 (s, 3H, SO2CH3, 4-(methylsulfonyl)phenyl); 3.442
(s, 3H, SO2CH3, 2-methylsulfonyl); 7.460–7.521 (m, 3H, ArH); 7.624–7.641
(m, 2H, ArH); 7.84(d, 2H, J = 8Hz, 3,5-(methylsulfonyl)phenyl); 7.96 (d, 2H,
J = 8Hz, 2,6-(methylsulfonyl)phenyl).
4-(4-(Methylthio)phenyl)-5-phenyl-1,3-dihydro-2H-[4-14C]
imidazole-2-thione-10
Sodium (117 mg) was added to dry methanol (2.1 mL) and mixed until
solid particles had dissolved. 2-Bromo-1-(4-(methylthio)phenyl)-2-
phenyl[1-14C]ethanone 9 (548 mg, 35 MBq) was poured into the sodium
methoxide solution, and 4 mL of dry methanol was added to the mixture.
The mixture was stirred under reflux for 2 h. Then the mixture was poured
into water and neutralized with cold 5% hydrochloric acid. Organic
compounds were extracted with ethyl acetate and dried over sodium
sulfate. The ethyl acetate was evaporated under reduced pressure.
The oily residue, which contained 2-hydroxy-1-(4-(methylthio)phenyl)-
2-phenyl[1-14C]ethanone 1, was used for the next reaction directly.
The mixture of crude product 1 and NH4SCN (1.289 g) and n-butanol
(4.5 mL) was refluxed for 2 h. Then water was added to the mixture,
and crude title compound 10 was extracted with ethyl acetate. The
extracted crude product was purified with silica gel column chro-
matography and ethyl acetate:n-hexane (20:80) as eluent. Overall
radiochemical yields (233 mg, 16 MBq) of two steps were 46%. 1HNMR
(CDCl3) δ(ppm): 2.526 (s, 3H, SCH3); 7.28(d, 2H, J = 8Hz, 3,5-methyl
sulfide phenyl); 7.3 (m, 3H, 3,4,5-phenyl); 7.41(d, 2H, J = 8Hz, 2,6-methyl
sulfide phenyl); 7.539 (b, 2H, 2,6-phenyl).
Conclusion
In this paper, we have presented a convenient synthetic pathway
for labeling of a series of 4,5-diarylimidazole with carbon-14 in
the 5-position of imidazole moiety by using 2-hydroxy-1-(4-
(methylthio)phenyl)-2-phenyl[1-14C]ethanone 1, an asymmetrical
benzoin as a key synthetic intermediate as shown in Scheme 2.
This article is dedicated to the memory of Dr.
Nader Saemian
The late doctor NADER SAEMIAN supervisor of the project
passed away before this plan was completed. We would like to
express our deep condolence over shocking news of his death
as he was one of the best friends of ours during all these years.
We will all miss him because of his great supports given to
current project and also for very good moments we had
together during research activities. We still cannot believe that
he is not among us anymore.
He was the greatest encouragement and a supportive mentor
whom we had ever seen in our entire life. His friendship,
kindness and knowledge are the main reasons which made us
to stand at this point. We will cherish all the happy memories
we had with him and hope his soul may rest in peace.
2-(Methylthio)-5-(4-(methylthio)phenyl)-4-phenyl-1H-[5-14C]
imidazole 11
Compound 10 (144 mg, 0.484 mmol, 10 MBq), methyl iodide (138 mg,
0.968 mmol), methanol (23.3 mL) and triethyl amine (100 μL) were
mixed and refluxed for 1 h. The solvent was removed in vacuo, and the
residue was purified by silica gel column chromatography by using
ethylacetate:hexane (20:80) as eluent to give the title compound 11
(113 mg, 7.5 MBq) in 75% yield. 1HNMR (CDCl3) δ(ppm): 2.503 (s, 3H,
SCH3, 4-(methylthio)phenyl); 2.720 (s, 3H, SCH3, 2-methylthio); 7.226–
7.258 (m, 4H, ArH); 7.308–7.368 (m, 3H, ArH); 7.539–7.585 (m, 2H, ArH).
2-(Methylsulfonyl)-5-(4-(methylsulfonyl)phenyl)-4-phenyl-
1H-[5-14C]imidazole 12
References
[1] J. F. Fries, S. R. Miller, P. W. Spitz, C. A. Williams, H. B. Hubert, D. A.
Bloch, Gastroenterology 1989, 96, 647.
[2] M. Langman, J. Weil, P. Wainwright, D. Lawson, M. Rawlins, R. Logan,
M. Murphy, M. Vessey, D. Colin-Jones, The Lancet 1994, 343, 1075.
[3] J. R. Vane, Nat. New Biol. 1971, 232.
To a stirred solution of Oxone (0.5 g) in water (10 mL), a solution of
compound 11 (60 mg, 4 MBq) in methanol (1.2 mL) and THF (0.6 mL)
was slowly added. The mixture was refluxed overnight, and the residue
was concentrated under reduced pressure and extracted with ethyl
J. Label Compd. Radiopharm 2016, 59 153–156
Copyright © 2016 John Wiley & Sons, Ltd.
www.jlcr.org

G. Shirvani et al.
[4] B. J. R. Whittle, G. A. Higgs, K. E. Eakins, S. Moncada, J. R. Vane, Nature [20] A. Assadieskandar, A. Amirhamzeh, M. Salehi, K. Ozadali, S. N. Ostad,
1980, 284, 271.
[5] J. Y. Fu, J. L. Masferrer, K. Seibert, A. Raz, P. Needleman, J. Biol. Chem. [21] A. K. Gadad, M. B. Palkar, K. Anand, M. N. Noolvi, T. S. Boreddy, J.
1990, 265, 16737. Wagwade, Bioorg. Med. Chem. 2008, 16, 276.
[6] W. Xie, J. G. Chipman, D. L. Robertson, R. Erikson, D. L. Simmons, Proc. [22] M. Salimi, M. Amini, A. Shafiee, Sulfur Silicon Relat. Elem. 2005,
A. Shafiee, M. Amini, Bioorg. Med. Chem. 2013, 21, 2355.
Natl. Acad. Sci. 1991, 88, 2692.
[7] M. K. O’Banion, H. B. Sadowski, V. Winn, D. A. Young, J. Biol. Chem.
1991, 266, 23261.
180, 1587.
[23] N. Saemian, G. Shirvani, H. Matloubi, J. Radioanal. Nucl. Chem. 2007,
274, 631.
[8] A. Pacelli, J. Greenman, C. Cawthorne, G. Smith, J. Label. Compd. [24] W. R. Vaughan, D. I. McCane, J. Am. Chem. Soc. 1954, 76, 2504.
Radiopharm. 2014, 57, 317.
[25] J. D. Roberts, C. M. Regan, J. Am. Chem. Soc. 1953, 75, 2069.
[26] K. Rorig, J. D. Johnston, R. W. Hamilton, T. J. Telinski, Org. Synth. 1963,
4, 576.
[9] P. Rao, E. E. Knaus, J. Pharm. Pharm. Sci. 2008, 11, 81.
[10] H. Yazdanpanah, Iranian Journal of Pharmaceutical Research: IJPR
2011, 10, 653.
[27] R. Adams, A. F. Thal, Org. Synth. 1941, 1, 436.
[11] H. Irannejad, A. Kebriaieezadeh, A. Zarghi, F. Montazer-Sadegh, A. [28] A. P. Black, F. H. Babers, Org. Synth. 1943, 2, 512.
Shafiee, A. Assadieskandar, M. Amini, Bioorg. Med. Chem. 2014, 22, 865.
[12] H. Ahmadzade Kermani, A. Shockravi, Z. Moosavi-Movahedi, A.
Khalafi-Nezhad, S. Behrouz, F.-Y. Tsai, G. H. Hakimelahi, A.
Seyedarabi, A. A. Moosavi-Movahedi, J. Iran. Chem. Soc. 2013,
10, 961.
[29] R. C. Fuson, N. Rabjohn, Org. Synth. 1955, 3, 557.
[30] P. Tundo, M. Selva, A. Bomben, Org. Synth, Vol 10, John Wiley & Sons,
Inc., 2004.
[31] V. R. Veeramaneni, M. Pal, K. R. Yeleswarapu, Tetrahedron 2003,
59, 3283.
[13] L. Navidpour, H. Shadnia, H. Shafaroodi, M. Amini, A. R. Dehpour, A.
[32] A. D. Gray, T. P. Smyth, J. Org. Chem. 2001, 66, 7113.
[33] N. Shimokawa, H. Nakamura, K. Shimakawa, H. Minami, H. Nishimura,
J. Med. Chem. 1979, 22, 58.
[34] B. S. Furniss, Vogel’s Textbook of Practical Organic Chemistry, 5 edn,
Editor: Pearson Education India, 1989.
Shafiee, Bioorg. Med. Chem. 2007, 15, 1976.
[14] L. Navidpour, H. Shafaroodi, K. Abdi, M. Amini, M. H. Ghahremani, A.
R. Dehpour, A. Shafiee, Bioorg. Med. Chem. 2006, 14, 2507.
[15] P. N. P. Rao, M. Amini, H. Li, A. G. Habeeb, E. E. Knaus, Bioorg. Med.
Chem. Lett. 2003, 13, 2205.
[35] Z. Diwu, C. Beachdel, D. H. Klaubert, Tetrahedron Lett. 1998, 39, 4987.
[16] H. Matloubi, A. Shafiee, N. Saemian, G. Shirvani, F. J. Daha, J. Label. [36] J. Hooz, J. N. Bridson, Can. J. Chem. 1972, 50, 2387.
Compd. Radiopharm. 2004, 47, 31.
[37] M. Kihara, M. Ikeuchi, K. Jinno, M. Kashimoto, Y. Kobayashi, Y. Nagao,
Tetrahedron 1993, 49, 1017.
[38] I. Moreno, I. Tellitu, E. Domínguez, R. SanMartín, Eur. J. Org. Chem.
2002, 2002, 2126.
[39] I. Pravst, M. Zupan, S. Stavber, Tetrahedron Lett. 2006, 47, 4707.
[40] K. Tanemura, T. Suzuki, Y. Nishida, K. Satsumabayashi, T. Horaguchi,
Chem. Commun. (Cambridge, U. K.) 2004, 470.
[41] G.-i. Tsuchihashi, K. Kitajima, S. Mitamura, Tetrahedron Lett. 1981,
22, 4305.
[17] C. K. Lau, C. Brideau, C. Chi Chung, S. Charleson, W. A. Cromlish, D.
Ethier, J. Y. Gauthier, R. Gordon, J. Guay, S. Kargman, C.-S. Li, P. Prasit,
D. Reindeau, M. Thérien, D. M. Visco, X. Lijing, Bioorg. Med. Chem.
Lett. 1999, 9, 3187.
[18] Y. Leblanc, P. Roy, S. Boyce, C. Brideau, C. C. Chan, S. Charleson, R.
Gordon, E. Grimm, J. Guay, S. Léger, C. S. Li, D. Riendeau, D. Visco,
Z. Wang, J. Webb, L. J. Xu, P. Prasit, Bioorg. Med. Chem. Lett. 1999,
9, 2207.
[19] T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S. Carter, P. W. Collins, S.
Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M. Miyashiro, R. S.
Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N.
Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins, K. Seibert, A. W.
Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med. Chem. 1997, 40, 1347.
[42] C. L. Stevens, W. Malik, R. Pratt, J. Am. Chem. Soc. 1950, 72, 4758.
[43] S. S. Jenkins, J. Am. Chem. Soc. 1934, 56, 682.
[44] W. S. Ide, J. S. Buck, Organic Reactions, Vol 4, John Wiley & Sons, Inc.,
1948, pp. 269.
[45] T. Nagano, J. Org. Chem. 1957, 22, 817.
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