Triaryl (Z)-olefins suitable for radiolabeling with carbon-11 or fluorine-18 radionuclides for positron emission tomography imaging of cyclooxygenase-2 expression in pathological disease

Article abstract of DOI:10.1016/j.bmcl.2010.06.155

A group of (Z)-1,1-diphenyl-2-(4-methylsulfonylphenyl)alk-1-enes were synthesized using methodologies that will allow incorporation of a [ ¹¹C]OCH₃ substituent at the para-position of the C-1 phenyl ring, a [¹¹C]SO₂

Full text of DOI:10.1016/j.bmcl.2010.06.155

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5245–5250
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Triaryl (Z)-olefins suitable for radiolabeling with carbon-11 or fluorine-18
radionuclides for positron emission tomography imaging
of cyclooxygenase-2 expression in pathological disease
*
Khaled R. A. Abdellatif, Carlos A. Velázquez, Zhangjian Huang, Morshed A. Chowdhury, Edward E. Knaus
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
a r t i c l e i n f o
a b s t r a c t
Article history:
A group of (Z)-1,1-diphenyl-2-(4-methylsulfonylphenyl)alk-1-enes were synthesized using methodolo-
gies that will allow incorporation of a [11C]OCH3 substituent at the para-position of the C-1 phenyl ring,
a [11C]SO2CH3 substituent at the para-position of the C-2 phenyl ring, a [18F]OCH2CH2F substituent at the
para-position of the C-1 phenyl ring, and a [18F]CH2CH2F substituent at the C-2 position of the olefinic
bond. The [11C] and [18F] radiotracers are designed as potential radiopharmaceuticals to image cycloox-
ygenase-2 (COX-2) expression in any organ where COX-2 is upregulated. The COX-1/COX-2 inhibition
data acquired suggest that compounds having a [11C]OMe or [18F]OCH2CH2F substituent at the para-posi-
tion of the C-1 phenyl ring may be more suitable for imaging COX-2 expression in view of their ability to
exclusively inhibit the COX-2 isozyme.
Received 10 June 2010
Revised 28 June 2010
Accepted 29 June 2010
Available online 23 July 2010
Keywords:
Tricyclic (Z)-olefins
Cyclooxygenase-2
Positron emission tomography imaging
Ó 2010 Elsevier Ltd. All rights reserved.
Positronemissiontomography(PET)isa valuablemedicalimaging
technique employing compounds labeled with a short-lived positron
emitting radioisotope (radiotracer) for quantitative investigations of
molecular and cellular transport processes in vivo. In this regard,
PET offers exceptional possibilities to study physiology, metabolism,
pharmacokineticsandmodesof actionofnovelandestablisheddrugs.
The most common positron emitters for this purpose include 11C
(t1/2 = 20.4 min) and 18F (t1/2 = 109.6 min). Being bioisosteric with
hydrogen, albeit with high electronegativity, 18F is often used to
replace hydrogen of otherwise non-fluorinated molecules with min-
imum effects on biomolecular interactions.1 The inducible isozyme
cyclooxygenase-2 (COX-2) is a relevant target for molecular imaging
since low levels of COX-2 are produced during normal cell function in
only a few tissues relative to COX-2 over expression that is associated
with pathological conditions in a much larger number of organs.2
COX-2expression causes a numberof undesirablepathophysiological
effectsthat includepain, inflammation,fever, CNSischemia,andCOX-
2 upregulation occurs in a variety of malignant tumors.3–6 Accord-
ingly, selective COX-2 inhibitors have, or may offer, potential for the
chemoprevention of various types of cancer such as colon, breast,
prostrate, stomach and pancreatic, wherein the over-expression of
COX-2 produces COX-2–derived prostaglandins (PGs) that stimulate
tumor growth.
expression. Although [11C]rofecoxib (1, see structure in Fig. 1)
showed a correlation between [11C]rofecoxib uptake and COX-2
distribution in healthy rats, it’s inability to unambiguously detect
COX-2 expression in rat inflammation models may have been
due to low affinity for the COX-2 isozyme.7 A [18F] derivative of
rofecoxib (2) has been synthesized as a potential PET radiotracer.8
The [18F] derivative of celecoxib (3) was synthesized as a potential
marker for COX-2 activity.9 Toyokuni et al. synthesized a [18F]oxa-
zole compound (4) as a potential radiotracer to image COX-2.10 The
CH2F moiety in 4 is metabolically labile. Synthesis of the radioio-
dinated COX-2 inhibitory potential SPECT radiotracers 511 and
612 have also been reported. Despite recognition of the potential
value of COX-2-targeted imaging agents such as 1–6, there is a
requirement for continued in vivo investigation using superior
agents to establish the clinical utility of this strategy.
A number of general structure–activity relationships (SARs) have
emerged for the tricyclic class of selective COX-2 inhibitors, viz: (i)
many selective COX-2 inhibitors have two vicinal (adjacent) aryl
substituents attached to a five- or six-membered central ring that
acts as a scaffold such as benzene, pyridine, thiophene, pyrrole,
imidazole, thiazole, cyclopentene, or pyrazole,13,14 (ii) para-substit-
uents on the adjacent aryl rings that provide optimal COX-2 selectiv-
ity, potency and oral activity are usually a COX-2 pharmacophore on
one ring (–SO2Me, –SO2NH2) and a F, Me or H substituent on the
other aryl ring,15 (iii) the para-position of the COX-2 pharmacophore
is critical for COX-2 selectivity since placement at the meta-position
of the aryl ring may abolish COX-2 activity,13 (iv) reversing the posi-
tion, or changing their position on the central ring (regioisomers) of
the two aryl moieties (Ar and 4-MeO2S(or H2NO2S)–C6H4–) can
A number of radiolabeled compounds have been prepared for
use as PET, or SPECT (single photon emission computed tomogra-
phy), radiotracers to image COX-2 and measure COX-2 over
* Corresponding author. Tel.: +1 780 492 5993; fax: +1 780 492 1217.
E-mail address: eknaus@pharmacy.ualberta.ca (E.E. Knaus).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.155

5246
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5245–5250
SO2CH3
SO211CH3
SO2CH3
N
N
F3C
O
O
O
O
18F
18F
3
2
1
R1
SO2NH2
SO2NH2
18FCH2
O
N
N
N
N
F3C
F3C
N
123I
125I
5 (R1 = SO2Me, SO2NH2)
6
4
Figure 1. Some examples of selective COX-2 inhibitory compounds designed as PET (1–4), or SPECT (5–6), radiotracers.
either abolish or enhance COX-2 inhibitory activity,14 (v) a lipophilic
MeO2S
Me
substituent (F, Me) at the para-position of one of the aryl rings usu-
ally enhances COX-2 inhibitory activity,15 and a SO2Me or SO2NH2
substituent at the para-position of one aryl ring usually provides
optimal COX-2 inhibitory potency,16 (vi) replacement of –SO2Me
by –SO2CF3, –COMe, –PO(OH)Me, –CO2H, –PO(OH)2 or –SO(@NH)Me
generally abolishes COX-2 inhibitory activity,17 (vii) an ortho-substi-
tuent on an aryl ring, which may distort the active orientation of the
two aryl rings, such as 2-MeO–C6H4–, may abolish COX-2 inhibitory
activity,16 (viii) potency, selectivity and in vivo efficacy are affected
by the substitution pattern on the aryl rings and the position of the
COX-2 pharmacophore (SO2Me, SO2NH2) moiety on an aryl ring may
be important in preventing oxidative metabolism,13 and (ix) the
lower log P for SO2NH2 versus SO2Me might improve absorption
and provide a more rapid onset of action.16
In an earlier study, we reported a novel group of acyclic triaryl
(Z)-olefins (7, see Fig. 2) that exhibit selective COX-2 inhibitory and
anti-inflammatory activities.18 Furthermore, this group of olefins 7
have a structural relationship to the selective estrogen receptor
antagonist (Z)-tamoxifen (8) that is used to treat hormone-respon-
sive breast cancers.19 The SARs described in the preceding para-
graph were used a guide to select putative positions (*) in the
Me
N
R1
Me
O
7, R1 = alkyl
(Z
)-tamoxifen (8)
O
R1 = Et, R2 = O*CH3, R3 = CH3
R1 = n-Bu, R2 = O*CH3, R3 = CH3
O
S
R2
R3
R1 = n-Bu, R2 = OCH2CH2*F, R3 = CH3
R1 = Et, R2 = H, R3 = *CH3
R1 = n-Bu, R2 = H, R3 = *CH3
R1 = CH2CH2*F, R2 = H, R3 = CH3
*Indicates position suitable for labelling
with a [11C] or [18F] radionuclide
R1
9
Figure 2. Someexamples oftricyclic (Z)-olefinsthatexhibitselectiveCOX-2inhibitory
andanti-inflammatory activities (7) andselective estrogenreceptor antagonistactivity
against hormone-responsive breast cancers (8), and the putative positions (*) where a
[
11C]- or [18F]-radionuclide may be incorporated for assessment as imaging agents to
target COX-2 expression or estrogen-responsive breast tumors (9).
MeO2S
OMe
MeO2S
OH
SO2Me
OH
b
a
R1
R1
O
R1
O
10a, R1= Et
10b, R1= n-Bu
12a, R1= Et
13a, R1= Et
11
12b, R1= n-Bu
13b, R1= n-Bu
c, for 12b
F
MeO2S
O
n-Bu
14
Scheme 1. Reagents and conditions: (a) Zn, TiCl4, THF, reflux 4.5 h; (b) 5 N NaOH, CH3I, DMF, 60 °C, 3 min; (c) (i) K2CO3, Kryptofix 222, CH3CN, 50 °C, 15 min; (ii) TsOCH2CH2F,
reflux 10 min.

K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5245–5250
5247
product (13a, R1 = Et, 36%; 13b, R1 = n-Bu, 31%). Alternatively,
condensation of the phenol 12b (R1 = n-Bu) with 2-fluoroethyl tos-
ylate (TsOCH2CH2F) in the presence of K2CO3 and Kryptofix 222
with MeCN as solvent at 50 °C with a 15 min reaction time yielded
the 2-fluoroethoxyphenyl product 14 in 51% yield. Similar reac-
tions of the phenols (12a–b) with [11C]CH3I, or [18F]TsOCH2CH2F
will provide a suitable method to synthesize the respective [11C]
and [18F] labeled radiopharmaceuticals.
O
O
Me
S
NaO
S
O
a
b
R1
R1
The replacement of natural abundance 12C by 11C in a methyl-
sulfonyl (CH3SO2) COX-2 pharmacophore is particularly attractive
since the physical chemical, biodistribution and biological proper-
ties of the molecule will not be changed. Accordingly, the CH3SO2
substituent present in the methylsulfonyl compounds 15a–b was
elaborated to the respective sodium sulfinates (16a, R1 = Et, 50%;
16b, R1 = n-Bu, 42%) by sequential treatment with the Grignard re-
agent MeMgCl and then (n-Bu)3B using a procedure similar to that
reported by de Vries et al.7 (see Scheme 2). The sodium sulfinates
(16a–b) are stable readily isolated products that upon treatment
with CH3I in DMF at 90 °C with a 5 min reaction time afford the
respective methylsulfonyl compound (15a, R1 = Et, 41%; 15b,
R1 = n-Bu, 49%). Similar reactions of the sodium sulfinates (16a–
b) with [11C]CH3I constitute a viable method to synthesize the
respective [11C]labeled radiopharmaceuticals.
16a, R1= Et
15a, R1= Et
16b, R1= n-Bu
15b, R1= n-Bu
Scheme 2. Reagents and conditions: (a) (i) CH3MgCl, THF, reflux 2 h; (ii) (n-Bu)3B,
reflux 18 h; (iii) aqueous Na2CO3; (b) CH3I, DMF, 90 °C, 5 min.
tricyclic (Z)-olefins (9) at which a [11C]- or [18F]-radionuclide could
be incorporated for assessment as imaging agents to target COX-2
expression or estrogen-responsive breast tumors in future investi-
gations. We now describe non-radioactive synthetic methodolo-
gies that will be applicable to the future radiochemical synthesis
of the putative radiopharmaceuticals
9 employing reaction
conditions and reagents that employ the corresponding [11C]- or
[
18F]-reagents.
Access to [18F]radiotracers with a longer radionuclide half-life
(t1/2 = 109.6 min) is highly relevant since it provides an extended
time period, compared to [11C] with a t1/2 = 20.4 min, during which
optimal imaging can be carried out based on the biodistribution
and elimination properties of the radiotracer being investigated.
It was therefore of interest to develop a methodology to incorpo-
rate a fluorine atom into a C-2 alkyl substituent as illustrated for
the 2-fluoroethyl compound 24 in Scheme 3. In this regard, the
AlCl3 catalyzed Freidel–Crafts acylation of thioanisole (17) with
b-chloropropionyl chloride furnished the ketone (18, 76%) which
was subsequently oxidized to the methylsulfonyl product
The (Z)-1-(4-hydroxyphenyl)-1-phenyl-2-(4-methylsulfonyl-
phenyl)alkenes (12a–b) were synthesized using a McMurry olefin-
ation reaction by Zn–TiCl4 catalzyed reductive cross-coupling of a
4-(methylsufonyl)alkanophenone (10, R1 = Et, n-Bu) with 4-
hydroxybenzophenone (11) in good yields (71–72%) as illustrated
in Scheme 1. These cross-coupling reactions of two aryl ketones
functionalized by a sulfonyl and hydroxyl substituent proceed in
a stereocontrolled manner to afford the target (Z)-olefinic products
according to the mechanism previously reported.18,20 The subse-
quent reaction of the phenols (12a–b) with MeI in the presence
of 5 N NaOH at 60 °C for 3 min afforded the respective methoxy
SMe
SMe
SO2Me
a
b
c
O
17
O
Cl
Cl
O
19
20
18
MeO2S
MeO2S
MeO2S
d
f
e
Cl
O
S
HO
21
O
O
22
MeO2S
MeO2S
23
NO2
F
24
25
Scheme 3. Reagents and conditions: (a) ClCH2CH2COCl, AlCl3, CHCl3, 25 °C, 1.5 h; (b) oxone (potassium peroxymonosulphate), MeOH, THF, H2O, 25 °C, 18 h; (c) Zn, TiCl4, THF,
reflux 4.5 h; (d) FeSO4ꢀ5H2O, DMSO, H2O, 130 °C, 48 h; (e) 4-nitrobenzenesulphonyl chloride, CH2Cl2, 0 °C, 2 h; (f) KF, Kryptofix 222, CH3CN, 90 °C, 10 min.

5248
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5245–5250
Table 1
C-1 phenyl ring may be more suitable for imaging COX-2 expres-
sion in view of their ability to exclusively inhibit the COX-2
isozyme.
In vitro COX-1 and COX-2 inhibition data for
methylsulfonylpheny)alkenes 12a–b, 13a–b, 14, 15a–b, and 24
a group of 1,2-diphenyl-2-(4-
O
O
S
R2
Me
Acknowledgment
We are grateful to the Canadian Institutes of Health Research
(CIHR) (MOP-14712) for financial support of this research.
R1
References and notes
R1
R2
IC50
COX-1
(lM)
COX-2 S.I.b
a
Compd
1. O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
2. Bazan, N. G. Nat. Med. 2001, 7, 414.
COX-2
12a
12b
13a
Et
n-Bu
Et
n-Bu
n-Bu
Et
OH
OH
OMe
OMe
OCH2CH2F
H
H
H
>100
>100
>100
>100
>100
31.6
9.1
>100
11.8
10.7
7.7
22.3
1.2
2.7
>100
0.065
—
3. Hinz, B.; Brune, K. J. Pharmacol. Exp. Ther. 2002, 300, 367.
4. Garavito, R. M. Nat. Struct. Biol. 1996, 3, 897.
5. Crofford, L. J. J. Rheumatol. 1997, 24, 15.
6. Dannenberg, A. J.; Lippman, S. M.; Mann, J. R.; Subbaramaiah, K.; DuBois, R. N. J.
Clin. Oncol. 2005, 23, 254.
7. de Vries, E. F. J.; Doorduin, J.; Dierckx, R. A.; van Waarde, A. Nucl. Med. Biol.
2008, 35, 35.
8. Wust, F. R.; Hohne, A.; Metz, P. F. Org. Biomol. Chem. 2005, 3, 503.
9. McCarthy, T. J.; Sheriff, A. U.; Graneto, M. J.; Talley, J. J.; Welch, M. J. J. Nucl. Med.
2002, 43, 117.
>8.5
>9.3
>13.0
>4.5
26.3
3.4
13b
14
15ac
15b
24
n-Bu
CH2CH2F
>100
115.9
—
1783
Celecoxib
a
10. Toyokuni, T.; Kumar, J. S. D.; Walsh, J. C.; Shapiro, A.; Talley, J. J.; Phelps, M. E.;
Herschman, H. R.; Barrio, J. R.; Satyamurthy, N. Bioorg. Med. Chem. Lett. 2005,
15, 4699.
11. Kuge, Y.; Katada, Y.; Shimonaka, S.; Temma, T.; Kimura, H.; Kiyono, Y.; Yokota,
C.; Minematsu, K.; Seki, K.; Tamaki, N.; Ohkura, K.; Saji, H. Nucl. Med. Biol. 2006,
33, 21.
The in vitro test compound concentration required to produce 50% inhibition of
ovine COX-1 or human recombinant COX-2. The result (IC50 M) is the mean of two
,
l
determinations acquired using the enzyme immuno assay kit (Catalog No. 560131,
Cayman Chemicals Inc., Ann Arbor, MI, USA) and the deviation from the mean is
<10% of the mean value.
b
In vitro COX-2 selectivity index (COX-1 IC50/COX-2 IC50).
12. Kabalka, G. W.; Mereddy, A. R.; Schuller, H. M. J. Labelled Compd. Radiopharm.
2005, 48, 295.
c
Data acquired using ovine COX-2 (Catalog No. 56101, Cayman Chemical Inc.).18
13. Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro, J. M.; Koboldt, C. M.;
Veenhuizen, A. W.; Currie, J. L.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40,
1619.
14. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
15. Pinto, D. J. P.; Copeland, R. A.; Covington, M. B.; Pitts, W. J.; Batt, D. G.; Orwat,
M. J.; Lam, G. N.; Joshi, A.; Chan, Y.-C.; Wang, S.; Trzaskos, J. M.; Magolda, R. L.;
Kornhauser, D. M. Bioorg. Med. Chem. Lett. 1996, 6, 2907.
16. Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J.; Collins, P. W.; Koboldt,
C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang, Y.
Y.; Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1634.
17. (a) Li, J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Collins, J. T.; Garland, D.
J.; Gregory, S. A.; Huang, H.-C.; Isakson, P. C. J. Med. Chem. 1995, 38, 4570; (b) Li,
J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Collins, J. T.; Garland, D. J.;
Gregory, S. A.; Huang, H.-C.; Isakson, P. C. J. Med. Chem. 1996, 39, 1846.
18. Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E. Bioorg. Med. Chem. 2004, 12, 5929.
19. Bedford, G. R.; Richards, D. N. Nature 1966, 212, 733.
20. Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E. Synlett 2004, 1513.
21. Experimental procedures and spectral data for compounds 12a–b, 13a–b, 14,
15a–b,16a–b, 19a–b, 21–25. General: Melting points were determined on a
Thomas–Hoover capillary apparatus and are uncorrected. Infrared (IR) spectra
were recorded as films on NaCl plates using a Nicolet 550 Series II Magna FT-IR
spectrometer. 1H NMR and 13C NMR spectra were measured on a Bruker AM-
300 spectrometer in CDCl3, CD3OD, or CDCl3 + CD3OD with TMS as the internal
standard, where J (coupling constant) values are estimated in Hertz (Hz). Mass
(19, 96%) using potassium peroxymonosulfate (Oxone) as an oxi-
dant (see Scheme 3). The McMurry Zn–TiCl4 catalzyed reductive
cross-coupling reaction of the ketone 19 with benzophenone (20)
afforded the 2-chloroethyl olefin (21, 50%), which on subsequent
reaction with FeSO4ꢀ5H2O at 130 °C afforded the 2-hydroxyethyl
product (22, 56%). Reaction of the alcohol 22 with 4-nitro-
benzenesulfonyl chloride furnished the 4-nitrobenzenesulfonate
(23, 63%). Nucleophilic displacement of the 4-nitrobenzenesulfo-
nate moiety present in 23 using KF in Kryptofix 222 at 90 °C with
a reaction time of 10 min afforded the target 2-fluoroethyl product
24 in 10% yield. This lower than expected yield is attributed to the
fact that the 2-fluoroethyl product 24 undergoes a facile elimina-
tion of HF to yield the C-2 vinyl product 25 (60%). Optimization
of the reaction conditions employed to minimize the formation
of the vinyl product 25 during the synthesis of [18F]labeled 24
did not warrant investigation since the 2-fluoroethyl compound
24 was an inactive inhibitor of the COX-1 and COX-2 isozymes at
a test compound concentration of 100 lM.
In vitro COX-1/COX-2 enzyme inhibition studies (see data in
Table 1) provided a number of structure–activity relationships
(SARs) viz (i) compounds 13a–b (R2 = OMe) and 14
(R2 = OCH2CH2F) having a substituent at the para-position of the
C-1 phenyl ring exhibited selective COX-2 inhibitory activity since
spectra (MS) were recorded on
spectrometer using the electrospray (ES) ionization mode. Microanalyses
were performed for C, by the Microanalytical Service Laboratory,
a Water’s Micromass ZQ 4000 mass
H
Department of Chemistry, University of Alberta and were within 0.4% of
theoretical values. Silica gel column chromatography was performed using
Merck Silica Gel 60 ASTM (70–230 mesh). All other reagents, purchased from
the Aldrich Chemical Company (Milwaukee, WI), were used without further
purification. The 4-(methylsulfonyl)alkanophenones (10a–b),18 2-fluoroethyl
p-toluenesulphonate23 and 1,1-diphenyl-2-(4-methylsulfonylphenyl)alkyl-1-
enes (15a–b)18 were prepared according to literature procedures. The chemical
no inhibition of COX-1 was observed at 100
lM (COX-1 IC50
>100
l
M), ii) compounds 15a–b having a R2 = H substituent, which
also inhibited the COX-1 isozyme, were the most potent COX-2
inhibitors, (iii) incorporation of a fluorine atom at the terminal po-
sition of a C-2 ethyl substituent abolished both COX-1 and COX-2
inhibitory activity (24, R1 = CH2CH2F COX-1 and COX-2 IC50’s
>100 lM), and (iv) binding affinity data of these putative radiotra-
cers with COX-2 would provide useful information relevant to
name
for
K222
(Kryptofix
222)
is
1,10-diaza-4,7,13,16,21,24-
hexaoxabicyclo[8.8.8]hexacosane.
General procedure for the synthesis of 1-(4-hydroxyphenyl)-1-phenyl-2-(4-
methylsulfonyl-phenyl)alkenes (12a–b): Titanium tertrachloride (1.83 mL,
13 mmol) was added dropwise to a stirred suspension of Zn powder (1.7 g,
26.5 mmol) in dry THF (30 mL) under an argon atmosphere at ꢁ10 °C, and this
mixture was heated at reflux for 2 h to produce the titanium reagent. A cooled
suspension of this titanium reagent was added to a solution of the respective 4-
(methylsulfonyl)alkanophenone (10a or 10b, 3.3 mmol) and 4-
hydroxybenzophenone (11, 0.65 g, 3.3 mmol) in THF (65 mL) at 0 °C, and the
reaction was allowed to proceed at reflux for 2.5 h. After cooling to 25 °C, the
reaction mixture was poured into a 10% aqueous K2CO3 solution (100 mL), this
mixture was stirred vigorously for 5 min, and the dispersed insoluble material
imaging studies.
In conclusion, (i) synthetic methodologies21 suitable for the
synthesis of the putative [11C] and [18F]labeled radiotracers illus-
trated in Figure 2 have been developed, and ii) COX-1/COX-2 inhi-
bition data22 suggest that compounds having a [11C]OMe (13a–b)
or [18F]OCH2CH2F (14) R1 substituent at the para-position of the

K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5245–5250
5249
was removed by vacuum filtration through a Celite 545 pad. The organic
fraction was separated, the aqueous layer was extracted with EtOAc
(3 ꢂ 50 mL), and the combined organic fractions were dried (Na2SO4).
Removal of the solvent in vacuo afforded a residue which was purified by
silica gel column chromatography using EtOAc–hexane (2:1, v/v) as eluent
followed by recrystallization of the product from EtOAc–hexane. Physical and
spectral data for 12a–b are listed below.
MeMgCl (2 mL, 6 mmol) in THF was added and the mixture was heated at
reflux for 2 h. After cooling to 25 °C, a solution of 1 M tri-n-butylborane in THF
(6 mL, 6 mmol) was added, and the mixture was heated at reflux for 21 h. After
cooling, the mixture was poured into diethyl ether (250 mL), the precipitate
was filtered and then dissolved in THF–H2O (2:1, v/v; 30 mL), and aqueous
Na2CO3 was added until the pH was 12. The precipitated magnesium salts were
filtered, the filtrate was evaporated to dryness, the residue was extracted with
methanol (25 mL), and removal of the methanol in vacuo furnished the
respective product 16a or 16b. Physical and spectral data for 16a–b are listed
below.
Sodium 4-(1,1-diphenylbut-1-en-2-yl)phenyl sulfinate (16a): Yield, 50%; white
powder; mp >300 °C; 1H NMR (CD3OD): d 0.89 (t, J = 7.3 Hz, 3H, CH2CH3), 2.47
(q, J = 7.3 Hz, 2H, CH2CH3), 6.85–6.88 (m, 2H, phenyl hydrogens), 6.94–6.97 (m,
3H, phenyl hydrogens), 7.17–7.37 (m, 7H, phenyl hydrogens, phenyl sulfinate
H-2, H-6), 7.46 (d, J = 8.5 Hz, 2H, phenyl sulfinate H-3, H-5); 13C NMR (CDCl3): d
13.8, 29.9, 124.9, 126.9, 127.8, 128.4, 129.2, 130.3, 130.9, 131.7, 140.9, 142.9,
144.2, 144.7, 144.9, 155.1; MS m/z (ES+) 393.1, C22H19Na2O2S (M+Na) requires
393.44.
Sodium 4-(1,1-diphenylhex-1-en-2-yl)phenyl sulfinate (16b); Yield, 42%; white
powder; mp >300 °C; 1H NMR (CD3OD): d 0.70 (t, J = 7.3 Hz, 3H, CH2CH3), 1.09–
1.22 (m, 4H, (CH2)2CH3), 2.38 (t, J = 7.3 Hz, 2H, C@C–CH2), 6.81–6.84 (m, 2H,
phenyl hydrogens), 6.89–6.95 (m, 3H, phenyl hydrogens), 7.12–7.32 (m, 7H,
phenyl hydrogens, phenyl sulfinate H-2, H-6), 7.41 (d, J = 8.6 Hz, 2H, phenyl
sulfinate H-3, H-5); 13C NMR (CDCl3): d 14.2, 23.8, 32.1, 36.6, 124.8, 126.9,
127.7, 128.5, 129.2, 130.4, 130.8, 131.6, 141.2, 141.8, 144.2, 144.7, 145.2,
155.0; MS m/z (ES+) 421.1, C24H23Na2O2S (M+Na) requires 421.49.
(Z)-1-(4-Hydroxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene (12a):
Yield, 71%; white crystals; mp 192–193 °C (lit.18 mp 188–190 °C); IR (film):
3417 (O–H), 2961 (C–H aromatic), 2926 (C–H aliphatic), 1308, 1148 (SO2)
cmꢁ1
;
1H NMR (CDCl3): d 0.93 (t, J = 7.3 Hz, 3H, CH2CH3), 2.50 (q, J = 7.3 Hz, 2H,
CH2CH3), 3.04 (s, 3H, SO2CH3), 4.75 (br s, 1H, OH, exchangeable with D2O), 6.48
(d, J = 8.5 Hz, 2H, 4-hydroxyphenyl H-3, H-5), 6.71 (d, J = 8.5 Hz, 2H, 4-
hydroxyphenyl H-2, H-6), 7.22–7.37 (m, 7H, phenyl hydrogens, 4-
methylsulfonylphenyl
H-2,
H-6),
7.75
(d,
J = 8.5 Hz,
2H,
13.3, 28.5,
4-
methylsulfonylphenyl H-3, H-5); 13C NMR (CDCl3 + CD3OD):
d
44.2, 114.4, 126.6, 127.4, 128.0, 129.2, 130.6, 131.8, 133.3, 137.1, 139.5, 140.9,
142.4, 149.2, 155.1; MS m/z (ES+) 379.1, C23H23O3S (M+H) requires 379.48.
(Z)-1-(4-Hydroxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)hex-1-ene (12b):
Yield, 72%; white crystals; mp 171–172 °C; IR (film): 3416 (O–H), 2958 (C–H
aromatic), 2921 (C–H aliphatic), 1314, 1146 (SO2) cmꢁ1 1H NMR (CDCl3): d
;
0.78 (t, J = 7.3 Hz, 3H, CH2CH3), 1.20–1.32 (m, 4H, (CH2)2CH3), 2.45 (t, J = 7.3 Hz,
2H, C@C–CH2), 3.05 (s, 3H, SO2CH3), 4.63 (br s, 1H, OH, exchangeable with
D2O), 6.49 (d, J = 8.5 Hz, 2H, 4-hydroxyphenyl H-3, H-5), 6.70 (d, J = 8.5 Hz, 2H,
4-hydroxyphenyl H-2, H-6), 7.21–7.39 (m, 7H, phenyl hydrogens, 4-
methylsulfonylphenyl
H-2,
H-6),
7.74
(d,
J = 8.5 Hz,
2H,
4-
methylsulfonylphenyl H-3, H-5); 13C NMR (CDCl3): d 13.8, 22.8, 31.1, 35.4,
44.5, 114.6, 126.9, 127.6, 128.2, 129.2, 130.6, 132.0, 134.6, 137.6, 138.9, 140.8,
142.8, 149.2, 155.1; MS m/z (ES+) 407.1, C25H27O3S (M+H) requires 407.54.
General procedure for the synthesis of 1-(4-methoxyphenyl)-1-phenyl-2-(4-
methylsulfonyl-phenyl)alkenes (13a–b): Methyl iodide (0.02 mL, 0.3 mmol)
General
procedure
for
preparation
of
1,1-diphenyl-2-(4-
methylsulphonylphenyl)alk-1-enes (15a–b) from sodium sulfinate salts (16a–b):
The sodium sulfinate salt (16a or 16b, 0.25 mmol) was dissolved in DMF (5 mL)
and methyl iodide (0.032 lL, 0.5 mmol) was added at 25 °C under argon, and
the mixture was heated at 90 °C for 5 min with stirring. Water (5 mL) was
added and the mixture was extracted with EtOAc (3 ꢂ 20 mL). The combined
organic extracts were successively washed with water (2 ꢂ 15 mL) and brine
(15 mL) prior to drying the organic fraction (Na2SO4). The solvent was
evaporated and the residue obtained was purified by silica gel column
chromatography using EtOAc–hexane (1:2, v/v) as eluent to give the
was added to
a stirred mixture of the respective phenol (12a or 12b,
0.25 mmol) and 5 N NaOH (0.06 mL, 0.3 mmol) in DMF (3 mL) under an
argon atmosphere, and this mixture was heated at 70 °C for three minutes.
After cooling to 25 °C, crushed ice (20 g) was added, the precipitate that formed
was separated and purified by silica gel column chromatography using EtOAc–
hexane (2:1, v/v) as eluent, and the product was recrystallized from EtOAc–
hexane. Physical and spectral data for 13a–b are listed below.
respective methyl sulphone 15a or 15b as
a white powder which
recrystallized as white clusters from EtOAc–hexane (yield 41%; mp 120–
122 °C; lit.18 mp 124–126 °C for 15a; yield 49%; mp 84–86 °C; lit.18 mp 79–
81 °C for 15b).
(Z)-1-(4-Methoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene (13a):
Yield, 36%; white crystals; mp 96–98 °C; IR (film): 2964 (C–H aromatic),
2929 (C–H aliphatic), 1314, 1149 (SO2) cmꢁ1
;
1H NMR (CDCl3): d 0.92 (t,
b-Chloroethyl p-methylthiophenyl ketone (18): 3-Chloropropionyl chloride
(1.38 mL, 14.4 mmol) was added dropwise to a stirred suspension of AlCl3
(1.76 g, 13.2 mmol) in chloroform (10 mL). Thioanisole (17, 1.38 g, 11.1 mmol)
was added at 0 °C and the reaction was allowed to proceed with stirring for
1.5 h at 25 °C. Water (10 mL) was added slowly at 0 °C, the organic layer was
separated, and the aqueous layer was extracted with EtOAc (3 ꢂ 10 mL). The
combined organic fractions were washed with water (10 mL), dried (Na2SO4),
and the solvent was removed in vacuo. The residue was recrystallized from
CH2Cl2–n-hexane (1:9, v/v) to afford 18 as pale red crystals in 76% yield; mp
113–115 °C (lit.24 mp 111–113 °C); IR (film): 2956 (C–H aromatic), 2916 (C–H
J = 7.3 Hz, 3H, CH2CH3), 2.50 (q, J = 7.3 Hz, 2H, CH2CH3), 3.04 (s, 3H, SO2CH3),
3.70 (s, 3H, OCH3), 6.57 (d, J = 8.5 Hz, 2H, 4-methoxyphenyl H-3, H-5), 6.76 (d,
J = 8.5 Hz, 2H, 4-methoxyphenyl H-2, H-6), 7.22–7.39 (m, 7H, phenyl
hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.75 (d, J = 8.5 Hz, 2H, 4-
methylsulfonylphenyl H-3, H-5); 13C NMR (CDCl3): d 13.5, 28.8, 44.4, 55.0,
113.1, 126.9, 127.0, 128.2, 129.2, 130.6, 131.8, 134.4, 137.7, 139.4, 140.7, 142.9,
149.0, 158.0; MS m/z (ES+) 393.2, C24H25O3S (M+H) requires 393.51. Anal. Calcd
for C24H24O3S: C, 73.44; H, 6.16. Found: C, 73.61; H, 6.35.
(Z)-1-(4-Methoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)hex-1-ene (13b):
Yield, 31%; white crystals; mp 95–97 °C; IR (film): 2961 (C–H aromatic),
aliphatic), 1670 (CO) cmꢁ1 1H NMR (CDCl3): d 2.54 (s, 3H, SCH3), 3.42 (t,
;
2924 (C–H aliphatic), 1313, 1146 (SO2) cmꢁ1
;
1H NMR (CDCl3): d 0.78 (t,
J = 7.3 Hz, 2H, CH2CH2Cl), 3.93 (t, J = 7.3 Hz, 2H, CH2CH2Cl), 7.28 (d, J = 8.6 Hz,
2H, m-phenyl hydrogens), 7.88 (d, J = 8.6 Hz, 2H, o-phenyl hydrogens).
J = 7.3 Hz, 3H, CH2CH3), 1.23–1.29 (m, 4H, (CH2)2CH3), 2.43 (t, J = 7.3 Hz, 2H,
C@C–CH2), 3.03 (s, 3H, SO2CH3), 3.70 (s, 3H, OCH3), 6.56 (d, J = 8.5 Hz, 2H, 4-
methoxyphenyl H-3, H-5), 6.75 (d, J = 8.5 Hz, 2H, 4-methoxyphenyl H-2, H-6),
7.21–7.37 (m, 7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.74
(d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5); 13C NMR (CDCl3): d 13.8,
22.7, 31.1, 35.4, 44.5, 55.0, 113.1, 127.0, 128.2, 129.2, 130.5, 130.7, 131.8, 134.5,
137.7, 138.3, 140.8, 142.9, 149.3, 158.0; MS m/z (ES+) 421.2, C26H29O3S (M+H)
requires 421.56. Anal. Calcd for C26H28O3S: C, 74.25; H, 6.71. Found: C, 74.30;
H, 6.71.
b-Chloroethyl p-methylsulphonylphenyl ketone (19):
A
solution of OxoneÒ
(potassium peroxymonosulfate, 4.06 g, 6.6 mmol) in water (20 mL) was
added to a stirred solution of b-chloroethyl p-methylthiophenyl ketone (9,
0.71 g, 3.3 mmol) in THF–MeOH (1:1, v/v; 10 mL) at 0 °C, and the reaction was
allowed to proceed with stirring for 18 h at 25 °C. Removal of the solvent in
vacuo gave a residue to which water (20 mL) was added. Extraction with EtOAc
(3 ꢂ 30 mL), washing the combined extracts with water (10 mL), drying the
organic fraction (Na2SO4), and removal of the solvent in vacuo gave a white
solid, which was purified by recrystallization from CH2Cl2–n-hexane (1:9, v/v)
to afford 19 as white crystals in 96% yield; mp 84–86 °C (lit.24 mp 85–87 °C); IR
(film): 2963 (C–H aromatic), 2926 (C–H aliphatic), 1696 (CO), 1314, 1153 (SO2)
(Z)-1-[4-(2-Fluoroethoxy)phenyl]-1-phenyl-2-(4-methylsulfonylphenyl)hex-1-ene
(14):
A
mixture
of
(Z)-1-(4-hydroxyphenyl)-1-phenyl-2-(4-
methylsulfonylphenyl)hex-1-ene (12b, 102 mg, 0.25 mmol), Kryptofix 222
(94 mg, 0.25 mmol) and anhydrous potassium carbonate (38 mg, 0.28 mmol)
in acetonitrile (3 mL) was heated at 50 °C for 15 min. 2-Fluoroethyl p-
toluenesulphonate (55 mg, 0.25 mmol) was added and the mixture was
heated under reflux for 10 min. After cooling to 25 °C, the solid was
separated by filtration, the filtrate was concentrated in vacuo, and the
residue was purified by silica gel column chromatography using EtOAc–
hexane (1:1, v/v) as eluent to give 14 as a white solid; Yield, 51%; mp 48–50 °C;
cmꢁ1 1H NMR (CDCl3): d 3.10 (s, 3H, SO2CH3), 3.51 (t, J = 6.7 Hz, 2H, CH2CH2Cl),
;
3.95 (t, J = 6.7 Hz, 2H, CH2CH2Cl), 8.09 (d, J = 8.6 Hz, 2H, o-phenyl hydrogens),
8.15 (d, J = 8.6 Hz, 2H, p-phenyl hydrogens).
4-Chloro-1,1-diphenyl-2-(4-methylsulphonylphenyl)but-1-ene
(21):
TiCl4
(1.83 mL, 13 mmol) was added dropwise to stirred suspension of Zn
a
powder (1.7 g, 26.5 mmol) in dry THF (30 mL) under an argon atmosphere at
ꢁ10 °C, and this mixture was heated at reflux for 2 h to produce the titanium
reagent. A cooled suspension of this titanium reagent was added to a solution
of b-chloroethyl p-methylsulphonylphenyl ketone (19, 0.82 g, 3.3 mmol) and
benzophenone (20, 0.60 g, 3.3 mmol) in THF (65 mL) at 0 °C, and the reaction
was allowed to proceed at reflux for 2.5 h. After cooling to 25 °C, the reaction
mixture was poured into a 10% aqueous K2CO3 solution (100 mL), this mixture
was stirred vigorously for 5 min, and the dispersed insoluble material was
removed by vacuum filtration through a Celite 545 pad. The organic fraction
was separated, the aqueous layer was extracted with EtOAc (3 ꢂ 50 mL), and
the combined organic fractions were dried (Na2SO4). Removal of the solvent in
IR (film): 2959 (C–H aromatic), 2928 (C–H aliphatic), 1312, 1150 (SO2) cmꢁ1
1H NMR (CDCl3):
0.79 (t, J = 7.3 Hz, 3H, CH2CH3), 1.23–1.27 (m, 4H,
;
d
(CH2)2CH3), 2.49 (t, J = 7.3 Hz, 2H, C@C–CH2), 3.06 (s, 3H, SO2CH3), 4.11 (ddd,
J = 28.0, J = 4.3, 4.3 Hz, 2H, OCH2CH2F), 4.70 (ddd, J = 48.0, J = 4.3, 4.3 Hz, 2H,
OCH2CH2F), 6.60 (dd, J = 6.7, 1.8 Hz, 2H, 4-fluoroethoxyphenyl H-3, H-5), 6.77
(dd, J = 6.7, 1.8 Hz, 2H, 4-fluoroethoxyphenyl H-2, H-6), 7.22–7.41 (m, 7H,
phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.75 (dd, J = 6.8, 1.8 Hz,
2H, 4-methylsulfonylphenyl H-3, H-5); 13C NMR (CDCl3): d 13.8, 22.7, 31.1,
35.4, 44.5, 66.8 (d, 2JCCF = 19.7 Hz), 81.8 (d, 1JCF = 171.4 Hz), 113.7, 126.9, 127.0,
128.2, 129.2, 130.5, 131.9, 135.1, 137.7, 138.6, 140.7, 142.8, 149.2, 156.8; MS
m/z (ES+) 453.2, C27H30FO3S (M+H) requires 453.58. Anal. Calcd for C27H29FO3S:
C, 71.65; H, 6.46. Found: C, 71.62; H, 6.58.
vacuo afforded
a residue, which was purified by silica gel column
chromatography using EtOAc–hexane (1:1, v/v) as eluent to give 21 as a
white solid (0.66 g, 50%); mp 141–143 °C; IR (film): 2962 (C–H aromatic), 2926
General procedure for the synthesis of sodium 4-(1,1-diphenylalk-1-en-2-yl)phenyl
sulfinate (16a–b): The methyl sulfone (15a or 15b, 1.0 mmol) was dissolved in
THF (15 mL) and the solution was cooled in an ice bath. A solution of 3 M
(C–H aliphatic), 1312, 1148 (SO2) cmꢁ1 1H NMR (CDCl3): d 3.00 (t, J = 7.3 Hz,
;
2H, CH2CH2Cl), 3.03 (s, 3H, SO2CH3), 3.40 (t, J = 7.3 Hz, 2H, CH2CH2Cl), 6.85–
6.88 (m, 2H, phenyl hydrogens), 7.01–7.06 (m, 3H, phenyl hydrogens), 7.26–

5250
K. R. A. Abdellatif et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5245–5250
7.42 (m, 7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.77 (d,
J = 8.0 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5); MS m/z (ES+) 397.1,
23H22ClO2S (M+H) requires 397.93.
KF (13.5 mg, 0.23 mmol) in acetonitrile (5 mL) was heated at 95 °C for 10 min.
After cooling to 25 °C, the solid was removed by filtration and discarded, the
solvent from the filtrate was removed in vacuo and the residue obtained was
purified by silica gel column chromatography using EtOAc–hexane (1:2, v/v) as
eluent to give 24 as a white solid (9 mg) and 25 as a yellow solid (50 mg).
Physical and spectroscopic data for 24 and 25 are listed below.
C
4-Hydroxy-1,1-diphenyl-2-(4-methylsulphonylphenyl)but-1-ene (22): A mixture
of 4-chloro-1,1-diphenyl-2-(4-methylsulphonylphenyl)but-1-ene (21, 397 mg,
1.0 mmol), and CuSO4ꢀ5H2O (250 mg, 1.0 mmol) in H2O–DMSO (1:3, v/v;
1.4 mL) was heated at 130 °C for 48 hours. After cooling to 25 °C, EtOAc (25 mL)
was added, the mixture was washed with H2O (3 ꢂ 10 mL), the organic phase
was dried (Na2SO4), and the solvent was removed in vacuo. The residue
obtained was purified by silica gel column chromatography using EtOAc–
hexane (2:1, v/v) as eluent to afford 22 as a white solid (212 mg, 56%); mp 164–
166 °C; IR (film): 3566–3215 (O–H), 2964 (C–H aromatic), 2928 (C–H
4-Fluoro-1,1-diphenyl-2-(4-methylsulphonylphenyl)but-1-ene (24): Yield, 10%;
white powder; mp 148–150 °C; IR (film): 2962 (C–H aromatic), 2906 (C–H
aliphatic), 1314, 1153 (SO2) cmꢁ1 1H NMR (CDCl3): d 2.97 (ddd, J = 22.6, 6.1,
;
6.1 Hz, 2H, CH2CH2F), 3.03 (s, 3H, SO2CH3), 4.37 (ddd, J = 47.6, 6.1, 6.1 Hz, 2H,
CH2CH2F), 6.88–6.89 (m, 2H, phenyl hydrogens), 7.04–7.06 (m, 3H, phenyl
hydrogens), 7.27–7.41 (m, 7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2,
H-6), 7.76 (dd, J = 8.4, 1.8 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5); 13C NMR
aliphatic), 1313, 1151 (SO2) cmꢁ1 1H NMR (CDCl3): d 2.81 (t, J = 7.3 Hz, 2H,
;
2
1
CH2CH2OH), 3.02 (s, 3H, SO2CH3), 3.59 (t, J = 7.3 Hz, 2H, CH2CH2OH), 6.85–6.88
(m, 2H, phenyl hydrogens), 7.01–7.05 (m, 3H, phenyl hydrogens), 7.26–7.40
(m, 7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.73 (d,
J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5); MS m/z (ES+) 379.1,
(CDCl3): d 36.4 (d, JCCF = 21.8), 44.4, 81.4 (d, JCF = 167.0), 126.8, 127.2, 127.3,
127.8, 128.4, 129.4, 130.4, 130.6, 133.2, 138.3, 141.6, 141.8, 144.8, 147.7; MS
m/z (ES+) 381.1, C23H22FO2S (M+H) requires 381.48. Anal. Calcd for
C
23H21FO2Sꢀ1/2H2O: C, 70.93; H, 5.69. Found: C, 71.02; H, 5.54.
C
23H23O3S (M+H) requires 379.48.
1,1-Diphenyl-2-(4-methylsulphonylphenyl)-2-(4-nitrophenylsulfonyloxyethyl)eth-
1-ene (23): mixture of the alcohol 22 (125 mg, 0.33 mmol), 4-
1,1-Diphenyl-2-(4-methylsulphonylphenyl)but-1,3-diene (25): Yield, 60%; yellow
powder; mp 114–116 °C; IR (film): 3020 (C–H aromatic), 2926 (C–H aliphatic),
A
1315, 1151 (SO2) cmꢁ1 1H NMR (CD3OD): d 3.08 (s, 3H, SO2CH3), 4.81 (dd,
;
nitrobenzenesulphonyl chloride (81 mg, 0.36 mmol), Et3N (0.09 mL,
0.66 mmol) and 4-dimethylaminopyridine (8 mg) in CH2Cl2 (3 mL) was
stirred at 0 °C for 2 h. The mixture was washed with H2O (5 mL), the organic
phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue
obtained was purified by silica gel column chromatography using EtOAc–
hexane (1:1, v/v) as eluent to furnish 23 as a white solid (117 mg, 63%); mp
178–179 °C; IR (film): 2962 (C–H aromatic), 2934 (C–H aliphatic), 1532, 1368
Jtrans = 17.5, Jgem = 2 Hz, 1H, CH@CHH0), 5.20 (dd, Jcis = 11.0, Jgem = 2 Hz, 1H,
CH@CHH0), 6.76 (dd, Jtrans = 17.5, Jcis = 11.0 Hz, 1H, CH@CHH0), 6.71–6.80 (m,
2H, phenyl hydrogens), 6.87–6.90 (m, 3H, phenyl hydrogens), 7.02–7.42 (m,
7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.79 (d, J = 8.5 Hz,
2H, 4-methylsulfonylphenyl H-3, H-5); 13C NMR (CD3OD): d 44.3, 118.7, 127.9,
128.7, 128.8, 129.2, 131.7, 131.8, 133.6, 138.7, 138.9, 140.1, 142.8, 143.3, 145.5,
147.7; MS m/z (ES+) 361.2, C23H21O2S (M+H) 361.47.
(NO2), 1350, 1185 (OSO2), 1312, 1150 (SO2) cmꢁ1
;
1H NMR (CDCl3): d 2.91 (t,
22. Cyclooxygenase inhibition assays: The ability of the test compounds listed in
J = 6.7 Hz, 3H, CH2CH2O), 3.03 (s, 3H, SO2CH3), 4.04 (t, J = 6.7 Hz, 3H, CH2CH2O),
6.82–6.85 (m, 2H, phenyl hydrogens), 7.03–7.06 (m, 3H, phenyl hydrogens),
7.20–7.40 (m, 7H, phenyl hydrogens, 4-methylsulfonylphenyl H-2, H-6), 7.71
(d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5), 7.95 (dd, J = 8.5, 1.9 Hz,
2H, 4-nitrophenyl H-2, H-6), 8.35 (dd, J = 8.5, 1.9 Hz, 2H, 4-nitrophenyl H-3, H-
5); MS m/z (ES+) 564.1, C29H26NO7S (M+H) requires 564.64.
4-Fluoro-1,1-diphenyl-2-(4-methylsulphonylphenyl)but-1-ene (24) and 1,1-
diphenyl-2-(4-methylsulphonylphenyl)but-1,3-diene (25): A mixture of the 4-
nitrophenylsulphonate 23 (130 mg, 0.23 mmol), K222 (87 mg, 0.23 mmol) and
Table 1 to inhibit ovine COX-1 and human recombinant COX-2 (IC50 value, lM)
was determined using an enzyme immuno assay (EIA) kit (Catalog no. 560131,
Cayman Chemical, Ann Arbor, MI, USA) according to our previously reported
method (Rao, P. N. P.; Amini, M.; Li, H.; Habeeb, A.; Knaus, E. E. J. Med. Chem.
2003, 46, 4872).
23. Howell, W. C.; Millington, J. E.; Patisson, F. L. M. J. Am. Chem. Soc. 1956, 78,
3843.
24. Bordwell, F. G.; Brannen, W. T. J. J. Am. Chem. Soc. 1964, 86, 4645.