Synthesis and cyclooxygenase inhibition of various (aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives

Article abstract of DOI:10.1016/j.bmc.2008.12.032

A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetyl

Full text of DOI:10.1016/j.bmc.2008.12.032

Bioorganic & Medicinal Chemistry 17 (2009) 1146–1151
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and cyclooxygenase inhibition of various
(aryl-1,2,3-triazole-1-yl)-methanesulfonylphenyl derivatives
b
c
c
b
Frank Wuest a, , Xinli Tang , Torsten Kniess , Jens Pietzsch , Mavanur Suresh
*
a Department of Oncology, University of Alberta, Edmonton, Canada
b Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada
c Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or
Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene
and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe2, 4-Cl, 4-F). All
compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic
and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relation-
ship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent
Received 30 October 2008
Revised 12 December 2008
Accepted 14 December 2008
Available online 24 December 2008
9
Keywords:
Click chemistry
Cyclooxygenase-1 and -2 inhibitors
Triazoles
COX-2 inhibition (IC50 = 0.03–0.36
lM) compared to their corresponding 1,3-diaryl-substituted counter-
parts (IC50 = 0.15 to >10.0 M). In both series, compounds possessing an electron-withdrawing group (Cl
l
and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selec-
tivity as determined for compounds containing electron-donating groups (Me, OMe, NMe2). The obtained
data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can
be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The
high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along
with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of com-
pounds interesting candidates for further design and synthesis of highly selective and potent COX-2
inhibitors.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
documented that especially COX-2 is overexpressed in many hu-
man cancer entities.5,6
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most
important class of widely used therapeutics for the treatment of
inflammation and pain. The principle pharmacological effects of
NSAIDs arise from their inhibition of cyclooxygenase enzymes.
Cyclooxygenases (COXs) control the complex conversion of arachi-
donic acid to prostaglandins and thromboxanes, which trigger as
autocrine and paracrine chemical messengers many physiological
and pathophysiological responses.1–3 COX is a membrane-bound
heme protein which exists in two distinct isoforms, a constitutive
form (COX-1) and an inducible form (COX-2). More recently, a no-
vel COX-1 splice variant termed as COX-3 has been reported.4 COX-
1 and COX-2 share the same substrates, produce the same products
and catalyze the same reaction using identical catalytic mecha-
nisms, but differ in substrate and inhibitor selectivity. The COX-1
enzyme is responsible for maintaining homeostasis (gastric and re-
nal integrity) whereas COX-2 induces inflammatory conditions. Be-
sides being associated with inflammation and pain, it is also well
Since the discovery of the COX-2 enzyme in the early 1990s,
many efforts have been made in the development of COX-2 selec-
tive inhibitors. Because of the structural similarities of the COX-1
and COX-2 enzymes, the search for selective inhibitors for COX-2
versus COX-1 represents a formidable challenge. A large number
of compounds has been investigated for selective COX-2 inhibition.
A common structural feature of many selective COX-2 inhibitors is
the presence of two vicinal aryl rings attached to a central 5-mem-
bered heterocyclic (compounds 1–4) or carbocyclic (compounds 5–
6) motif. A selection of different selective COX-2 inhibitors contain-
ing the diaryl 5-membered carbocycle/heterocycle scaffold is de-
picted in Figure 1.
Selective COX-2 inhibitors as shown in Fig. 1 demonstrate, that
a broad variety of 5-membered carbocycles and heterocycles are
acceptable for binding to the cyclooxygenase active site. A recent
review on the current status of COX-2 inhibitors further confirms
the flexibility of the carbocyclic/heterocyclic core motif for COX-2
binding.7 However, among the multitude of known 5-membered
heterocycles as selective COX-2 inhibitors, to the best of our
knowledge no 1,2,3-triazoles have been reported yet. 1,2,3-Tria-
zoles possess favorable properties for medicinal chemistry such
* Corresponding author. Tel.: +1 780 989 8150; fax: +1 780 432 8483.
E-mail address: frankwue@cancerboard.ab.ca (F. Wuest).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.12.032

F. Wuest et al. / Bioorg. Med. Chem. 17 (2009) 1146–1151
1147
SO2NH2
tuted 1,2,3-triazoles, also referred to as click chemistry, is among
the most exciting recent developments in medicinal chemistry.
An extension of the [3+2] cycloaddition click chemistry reaction
between organic azides and terminal alkynes was recently de-
scribed by Zhang and co-workers.10 They report on the use of
ruthenium(II) complexes instead of copper(I) for the cycloaddition
reaction, which led exclusively to the formation of the correspond-
ing 1,5-disubstituted 1,2,3-triazoles. We therefore decided to ex-
ploit both metal-catalyzed [3+2] cycloaddition reactions for the
construction of 1,2,3-triazoles containing either a 1,4- or 1,5-disub-
stitution pattern, respectively, as potential COX-2 inhibitors. For
this purpose we first prepared 1-azido-4-(methanesulfonyl)ben-
zene 9 as aromatic azide possessing the SO2Me COX-2 pharmaco-
phore for subsequent [3+2] cycloaddition reactions with various
commercially available para-substituted phenyl acetylenes. The
synthesis of aromatic azide 9 from commercially available 4-
(methylthio)aniline 7 was accomplished under mild conditions
with tert-butylnitrite and azidotrimethylsilane.13 4-(Methyl-
thio)aniline 7 undergoes diazotation with tert-butylnitrite at 0 °C.
The formed diazonium salt was easily converted into aromatic
azide 8 in the presence of azidotrimethylsilane at room tempera-
ture. Subsequent oxidation of 4-azido-thioanisole 8 with OxoneÒ
gave 1-azido-4-(methyl-sulfonyl)benzene 9 in excellent 95% yield
for both steps. The synthesis of compound 9 is illustrated in Fig-
ure 2.
F
H3C
MeO2S
MeO2S
N
N
S
O
O
CF3
Br
Celecoxib 2
Rofecoxib 3
SO2Me
DuP-697 1
SO2Me
H2NO2S
F
MeO
N
O
H3C
CH3
H3C
6
5
Valdecoxib 4
Figure 1. Selection of selective COX-2 inhibitors with
a
diaryl-substituted
5-membered carbocycle/heterocycle scaffold.
as a moderate dipole character, hydrogen bonding capability, rigid-
ity and stability under in vivo conditions.8
An exciting recent development in organic chemistry and
medicinal chemistry is the renaissance of the well-established
Huisgen [3+2] cycloaddition reaction between terminal alkynes
and azides through the introduction of copper and ruthenium com-
plexes to regioselectively catalyze 1,2,3-triazole formation. Appli-
cation of copper(I)-catalyzed [3+2] cycloaddition between azides
and alkynes affords 1,4-disubstituted 1,2,3-triazoles as the single
regioisomers, whereas the use of ruthenium complexes leads to
the formation of the corresponding 1,5-disubstituted 1,2,3-
triazoles.9,10
With aromatic azide 9 and a panel of various para-substituted
phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe2, 4-Cl, 4-F) in hand,
we performed two different click chemistry routes to prepare the
desired 1,4-diaryl-substituted triazoles 10a–f and 1,5-diaryl-
substituted triazoles 11a–f (Fig. 3).
In a first set of reactions, we employed the Cu(I)-catalyzed [3+2]
cycloaddition reaction between azide 9 and various phenyl acety-
lenes to prepare regioselectively triazoles 10a–f possessing a 1,4-
diaryl substitution pattern. For this purpose, equimolar amounts
of aryl acetylenes and azide 9 were reacted in a mixture of EtOH/
H2O in the presence 10 mol % CuI and triethylamine (TEA) at
60 °C for 24 h to give triazoles 10a–f in good yields (79–88%). All
compounds were obtained as pure solids without the need for fur-
ther purification. 1H NMR analysis showed a characteristic signal
between 8.13 Hz and 8.29 Hz, which is indicative of the proton in
1,2,3-triazoles containing the 1,4 substitution pattern.
We havean ongoinginterest in imagingCOX-2 functionalexpres-
sion in vivo by means of positron emission tomography (PET). For
this purpose, we have synthesized various COX-2 inhibitors labeled
with the short-lived positron emitters fluorine-18
(
18F,
t1/2 = 109.8 min)11 and carbon-11 (11C, t1/2 = 20.4 min).12 Recently,
we have reported on the synthesis and radiopharmacological evalu-
ation in vitro and in vivo of 11C-labeled compound 6 as potential PET
radiotracer for imaging COX-2. Despite the promising high affinity
and selectivity of compound 6 towards COX-2, however, the corre-
sponding 11C-labeled compound6 displayedunfavorableradiophar-
macological profile in rats and tumor-bearing mice, mainly due to
high metabolic instability and high nonspecific binding.12 In this
line, replacement of the central cyclopentene moiety with a 1,2,3-
triazole heterocyclic ring system should lead to compounds with
lower lipophilicity, which would improve radiopharmacological
profile through reduction of nonspecific binding in vivo.
Based on the intriguing finding that replacement of Cu(I) with
Ru(II) complexes for click chemistry between organic azides and
terminal alkynes leads to the formation of 1,5-substituted tria-
N N
In this paper, we report on the synthesis and in vitro COX-1 and
COX-2 inhibitory activity for a series of 1,4- and 1,5-diaryl substi-
tuted 1,2,3-triazoles possessing a SO2Me group as COX-2 pharma-
cophore at the para-position of one of the aryl rings. 1,4- and 1,5-
diaryl substituted 1,2,3-triazoles were synthesized by either Cu(I)-
catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions
between 1-azido-4-methane-sulfonylbenzene 9 and a panel of var-
ious para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-
NMe2, 4-Cl, 4-F).
CuI, TEA
N
SO2Me
R
N3
R
EtOH/H2O
60 ºC, 24 h
SO2Me
10d
, R = NMe2
10e, R = Cl
10f, R = F
10a
, R = H
9
10b, R = Me
+
10c
, R = OMe
N N
N
[Cp*RuCl(PPh3)2]
SO2Me
toluene,
120 ºC,12 h
11a
11d
Cp*
=
R
, R = H
, R = NMe2
11b, R = Me
11c
11e, R = Cl
11f, R = F
2. Chemistry
, R = OMe
The copper(I)-catalyzed [3+2] cycloaddition between terminal
alkynes and organic azides to form regiospecifically 1,4-disubsti-
Figure 3. Copper- and ruthenium-catalyzed [3+2] cycloaddition between aromatic
azide 9 and various phenyl acetylenes.
NH2
N3
N3
Oxone®
t-Bu-ONO, TMS-N3
MeS
CH3CN
MeS
THF/MeOH/H2O
MeSO2
7
8
9
Figure 2. Synthesis of 1-azido-4-(methylsulfonyl)benzene 9.

1148
F. Wuest et al. / Bioorg. Med. Chem. 17 (2009) 1146–1151
zoles, we set up a series of Ru-catalyzed reactions to afford 1,5-
substituted 1,2,3-triazoles 11a–f. According to literature, we
choose [Cp*RuCl(PPh3)2] as the most suitable ruthenium complex
for this reaction.10 Unlike the Cu(I)-catalyzed reaction, Ru(II)-cata-
lyzed click chemistry reaction between azide 9 and aryl acetylenes
required more drastic reaction conditions in an aprotic solvent
(toluene) at elevated temperature (120 °C). However, the desired
1,5-substituted 1,2,3-triazoles 11a–f were obtained in much lower
chemical yields (10–27%) compared to compounds 10a–f. More-
over, 1,5-substituted 1,2,3-triazoles 11a–f required purification
by means of flash chromatography to afford sufficiently pure com-
pounds. Consequently, the obtained low chemical yields, and the
tedious isolation and purification of compounds 11a–11 via
Ru(II)-catalyzed [3+2] cycloaddition reaction does not meet the cri-
teria of click chemistry as proposed by Kolb and Sharpless.8
The obtained low chemical yield is somewhat surprising, since
high chemical yields in the range of 80–94% were reported by
Zhang and co-worker.10 However, Zhang and co-worker were using
phenyl azide as the azide component, whereas in our reaction we
used more polar methylsulfone 9 as the aromatic azide component,
which may have an detrimental effect on the Ru(II)-catalyzed [3+2]
cycloaddition. The 1,5 substitution pattern was confirmed by the
characteristic high-field-shifted 1H NMR signals (7.78–7.88 Hz) as
typically observed for the 1,2,3-triazole ring proton in compounds
11a–f.10
acyclic triaryl (Z)-olefins,16 linear diaryl-substituted acetylenes,17
and diaryl-substituted isoindole derivatives showing an uncom-
mon 1,3-substitution pattern for the aryl rings.18
Based on two different metal-catalyzed [3+2] cycloaddition
reactions between 1-azido-4-methane-sulfonylbenzene 9 and var-
ious phenyl acetylenes, we have prepared two classes of com-
pounds possessing a central 1,2,3-triazole moiety. Performance of
the Cu(I)-catalyzed reaction exclusively yielded 1,4-diaryl 1,2,3-
triazoles 10a–f as single regioisomers. This class of compounds
exhibits a comparable molecule geometry as for various highly po-
tent and selective COX-2 inhibitors based on 1,3-diaryl-substituted
isoindoles.18 On the other hand, 1,5-diaryl-substituted compounds
11a–f having the preferred two vicinal aryl moieties, could be ob-
tained through Ru(II) complex-catalyzed reaction. This class of
compounds is structurally related to traditional selective COX-2
inhibitors consisting of a heterocyclic central ring scaffold with
two vicinal aryl substitutents.7 All compounds (10a–f and 11a–f)
possess the typical SO2Me COX-2 pharmacophore in the para-posi-
tion of one of the aryl rings attached to the central 1,2,3-triazole
unit. To determine the resulting combined different steric and elec-
tronic effects upon COX-1 and COX-2 inhibitory potency and COX
isoenzyme selectivity, all compounds were evaluated in in vitro
COX inhibition assays. Celecoxib 2 and compound 6 are known
highly potent and selective COX-2 inhibitors, which were used as
reference compounds.12,19 The determined enzyme inhibition data,
along with calculated in vitro COX-2 selectivity index (COX-2 SI)
and calculated lipophilicity values (LogPo/w) are summarized in
Table 1.
3. Results and discussion
As expected, compound 6 proved to be a potent and selective
COX-2 inhibitor in the performed enzyme inhibitory assay. The
determined inhibitory activity with IC50 value of 7 nM for COX-2
is in the same range as reported in the literature, whereas the
Various structure-activity relationship (SAR) studies have re-
vealed that tricyclic compounds possessing two vicinal aryl moie-
ties on the central heterocyclic ring system represent the major
class of selective COX-2 inhibitors.7 Moreover, the SO2Me COX-2
pharmacophore at the para-position of one of the aryl rings was
shown to frequently confer optimal COX-2 selectivity and po-
tency.14 However, various classes of compounds lacking the tradi-
tional tricyclic ring motif having a vicinal diaryl substitution
pattern have also been reported as potent and selective COX-2
inhibitors. Prominent examples comprise diarylurea derivatives,15
determined IC50 value of 5 lM against COX-1 is lower as in litera-
ture.19 For further comparison, we also determined COX-1 and
COX-2 inhibition of potent COX-2 inhibitor celecoxib 2.
The first series of compounds (10a–f) containing the uncom-
mon 1,3-disubstitution pattern of the aryl moieties showed inter-
esting results on the inhibitory activity depending on the
Table 1
In vitro COX-1 and COX-2 enzyme inhibition data
SO2NH2
N N
N N
N
N
H3C
SO2Me
SO2Me
SO2Me
R
N
N
10a-10f
11a-11f
6
Celecoxib
R
OMe
CF3
M)a
COX-2 IC50
0.07
(l
M)a
COX-2 SIb
LogPo/w
c
Compound
R
COX-1 IC50
(l
Celecoxib
6
7.7
110
715 (1980)d
139
18.0
4.0
—
64
59
7.5
6.5
4.9
2.3
17.5
30.3
3.01
4.21
1.84
2.30
1.66
1.95
2.41
1.87
1.84
2.30
1.66
1.95
2.41
1.87
5.0 (9.9)d
20.8
45.0
10.0
>100
12.2
12.5
0.81
0.78
0.83
0.84
0.70
0.91
0.007 (0.005)d
0.15
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
H
Me
OMe
NMe2
Cl
F
H
Me
OMe
NMe2
Cl
2.5
2.5
>10
0.19
0.21
0.11
0.12
0.17
0.36
0.04
0.03
F
a
Values are means of two determinations.
In vitro COX-2 selectivity index (IC50 COX-1/IC50 COX-2).
LogPo/w values have been calculated based on ACDLabs predictions.
Literature value, Ref. 19.
b
c
d

F. Wuest et al. / Bioorg. Med. Chem. 17 (2009) 1146–1151
1149
substituents at the para-position of one of the aryl rings. All com-
pounds of this series displayed only very low or no inhibitory po-
tency against the constitutive form of cyclooxygenase (COX-1) in
(LogPo/w) values in the range of 1.66–2.41. This lipophilicity range
is favorable for the further design of PET radiotracer with opti-
mized radiopharmacological profile for imaging COX-2. In this line,
the promising results on COX-2 inhibition selectivity and potency,
and lipophilicity of compounds 11e and 11f, make 1,2,3-triazole-
containing compounds interesting candidates for further develop-
ment of potent and selective COX-2 inhibitors, including radiotra-
cers for functional imaging of both COX-2 expression and activity
in vivo.
the range of 12.2 lM to >100 lM. A more differentiated picture
within compounds 10a–f was observed with regard to their inhibi-
tion against COX-2. Compounds (10b–d) containing large and elec-
tron-donating substituents (Me, OMe, NMe2) showed only very
low inhibition of the COX-2 enzyme as reflected by IC50 values in
the lM range (2.5 mM to >100 lM). On the other hand, smaller
(H, F, Cl) and electron-withdrawing (F, Cl) substituents in com-
pounds 10a, 10e and 10f gave IC50 values in the submicromolar
range (0.15–0.21 lM) and COX-2 SI values of 138 (R = H), 64
4. Conclusion
(R = Cl) and 59 (R = F), respectively, indicative of a selective and po-
tent COX-2 inhibition. The SI value of 138 makes compound 10a
the most COX-2 selective compound within all studied triazole-
containing compounds. According to these data, increasing size
and electron-donating properties of the para substituents, as found
for the Me, OMe, and NMe2 group in compounds 10b–d, decrease
COX-2 inhibitory potency. Thus, the tolerance of the para-position
at the aryl ring towards COX-2 inhibition potency seems to be lim-
ited mainly by the size of the substituents. This finding is in agree-
ment with literature reports also showing a reduced inhibitory
potency while increasing the size of the para substituent.18 The
second series of compounds (11a–f) contains the common vicinal
substitution pattern of potent and selective COX-2 inhibitors. Com-
pounds 11a–f displayed submicromolar COX-2 inhibitor potency,
whereas compounds 11e and 11f containing an electron-with-
drawing Cl or F substituent, behave as particularly highly potent
We have prepared a series of compounds based on a central
1,2,3-triazole scaffold having two aryl substituents as novel class
of COX-2 inhibitors. The geometric arrangement of the two aryl
rings attached to the 1,2,3-triazole moiety can easily be steered
by application of either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-
dipolar cycloaddition reaction. Compounds having a vicinal diaryl
substitution pattern showed more potent COX-2 inhibition com-
pared to their corresponding 1,3-diaryl-substituted counterparts.
In both series, compounds possessing an electron-withdrawing
group (Cl and F) at the para-position of one of the aryl rings dis-
played higher COX-2 inhibition potency as determined for com-
pounds containing electron-donating groups (Me, OMe, NMe2).
The obtained data show, that commonly used central carbocyclic
or heterocyclic ring system in COX-2 inhibitors can be replaced
by a central 1,2,3-triazole unit possessing a vicinal diaryl substitu-
tion pattern. The high COX-2 inhibition potency of some 1,2,3-tri-
azoles having a vicinal diaryl substitution pattern along with their
ease in synthesis through versatile Ru(II)-catalyzed click chemistry
make this class of compounds interesting candidates for further
design of highly selective and potent COX-2 inhibitors.
COX-2 inhibitors (IC50 = 0.04
pounds displayed moderate inhibitor activity towards COX-1
(IC50 = 0.70–0.91 M). Chlorine- and fluorine-substituted com-
lM and 0.03 lM). All these com-
l
pounds 11e and 11f are 3- to 12-fold more potent inhibitors com-
pared to compounds 11b, 11c and 11d having an electron-donating
group (Me, OMe or NMe2). Within this series, compounds 11e and
11f also showed the highest COX-2 selectivity (COX-2 SI = 17.5 and
30.3). The structure-activity relationship study of these com-
pounds indicated that the order of COX-2 inhibitory potency was
F > Cl > H > Me > OMe > NMe2. The order of COX-2 selectivity fol-
lowed the same order (F > Cl > H > Me > OMe > NMe2). This result
suggests that the presence of electron-withdrawing groups like
fluorine and chlorine favors selective and potent inhibition of
COX-2. Several reports in the literature upon the study of tricyclic
compounds possessing two vicinal aryl moieties on the central het-
erocyclic ring system support this observation.7
Direct comparison of compounds 10a–f and compounds 11a–f
further confirm the favorable vicinal diaryl substitution pattern
with regard to potent COX-2 inhibition. Compounds 11a–f, how-
ever, showed also moderate inhibitory activity against COX-1,
which was not the case for compounds 10a–f. Highly potent com-
pounds 11e and 11f are 5- to 6-fold more potent than their corre-
sponding 1,3-diaryl-substituted counterparts 10e and 10f. The
positive effect of the vicinal diaryl substitution on COX-2 inhibition
potency was even more pronounced for compounds 10b–d and
11b–d having electron-donating groups (Me, OMe, NMe2). Chang-
ing the 1,3-diaryl substitution pattern in compounds 10b–d to the
vicinal diaryl substitution pattern in compounds 11b–d is accom-
panied by a 20- to 30-fold increase in COX-2 inhibition potency.
Moreover, replacement of the central cyclopentene ring in ref-
erence compound 6 with a 1,2,3-triazole moiety as in compounds
10a–f and 11a–f resulted in a significant reduction of lipophilicity
by 2–2.5 orders of magnitude. Structurally related compounds 6
and 11c clearly demonstrate the lipophilicity-lowering effect of
the 1,2,3-triazole unit. The 1,2,3-triazole unit possesses a moderate
dipole character which allows additional hydrogen bonding
compared to the nonpolar cyclopentene unit in compound 6. All
novel 1,2,3-triazole-containing compounds displayed lipophilicity
5. Experimental
5.1. General
All commercial reagents and solvents were used without fur-
ther purification unless otherwise specified. Nuclear magnetic res-
onance spectra were recorded on
a Varian Unity 400 MHz
spectrometer. 1H NMR and 13C NMR chemical shifts were given
in ppm and were referenced with the residual solvent resonances
relative to tetramethylsilane (TMS). Melting points were deter-
mined on a Galen III melting point apparatus (Cambridge Instru-
ments) and are uncorrected. All compounds were analyzed for C,
H, N and S on a LECO CHNS 932 elemental analyzer. Elemental
analyses were within 0.4% for elements. Flash chromatography
was conducted according to Still et al.20 using MERCK silica gel
(mesh size 230–400 ASTM). Thin-layer chromatography (TLC)
was performed on Merck silica gel F-254 aluminum plates with
visualization under UV (254 nm). Compound 6 was prepared
according to literature procedure.12
5.2. Chemical synthesis
5.2.1. 1-Azido-4-(methyl-sulfonyl)benzene (9)
A solution of 4-(methylthio)aniline (1.32 ml, 10.75 mmol) in
CH3CN (40 ml) was cooled to 0 °C. tert-Butylnitrite (384
ll,
3.24 mmol) and azidotrimethylsilane (344 l, 2.6 mmol) were
l
added, and the mixture was warmed up to room temperature.
After stirring at room temperature for 2 h, the solvent was re-
moved under reduced pressure and the residue was dissolved in
diethyl ether. After extraction with water, the organic layer was
dried (Na2SO4) and the solvent was evaporated. The resulting oil
(1.8 g) was dissolved in a mixture of MeOH/THF (65 ml, 1:1) and
water (30 ml). OxoneÒ (7.5 g) was added and the mixture was stir-

1150
F. Wuest et al. / Bioorg. Med. Chem. 17 (2009) 1146–1151
red at room temperature overnight. After addition of water
(200 ml) and extraction with ethyl acetate, the organic layer was
passed through a silica gel plug. The solvent was evaporated under
reduced pressure to yield 2.04 g (96%) of compound 9 as a yellow
solid. Yield: 1H NMR (400 MHz, CDCl3): d 3.05 (s, 3H; SO2CH3),
7.18 (d, J = 8.8 Hz, 2H; Ar-H), 7.92 (d, J = 8.8 Hz, 2H; Ar-H).
JC–F = 8.4 Hz), 129.02, 132.51, 139.75, 140.29, 146.68, 162.23 (d,
JC–F = 244.2 Hz). Melting point: 249–253 °C.
5.2.3. General procedure for the Ru(II)-catalyzed synthesis of
triazoles
A mixture of 1-azido-4-methanesulfonylbenzene 9 (113.4 mg,
0.575 mmol), the respective aryl acetylene (0.632 mmol) and
[Cp*RuCl(PPh3)2] (6.9 mg, 8.6
lmol) in toluene (5 ml) was heated
5.2.2. General procedure for the Cu(I)-catalyzed synthesis of
triazoles
in a sealed vial under argon at 120 °C for 12 h. After evaporation
of the solvent, the residue was purified by flash-chromatography
(50% EtOAc/petroleum ether) to give the desired product as a solid.
A mixture of the respective aryl acetylene (0.575 mmol), CuI
(0.0575 mmol) and triethylamine (0.0575 mmol) in 15 ml of
EtOH/H2O (1:1) was thoroughly stirred at room temperature for
15 min. Then, 1-azido-4-methanesulfonylbenzene 9 (0.575 mmol)
in 5 ml of EtOH/H2O (1:1) was added and the resulting mixture
was stirred at 60 °C for 12 h. The formed precipitate was filtered
off, washed with water and diethylether. The sufficiently pure
products were dried in a desiccator over CaCl2.
5.2.3.1. 1-(4-Methanesulfonylphenyl)-5-phenyl-1H-[1,2,3]tria-
zole (11a). Yield: 22%. 1H NMR (400 MHz, CDCl3): d 3.09 (s, 3H;
SO2CH3), 7.22 (m, 2H; Ar-H), 7.40 (m, 3H; Ar-H), 7.58 (d,
J = 8.6 Hz, 2H; Ar-H), 7.87 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H; Ar-H).
13C NMR (100 MHz, CDCl3): d 44.30, 121.74, 125.38, 125.90,
127.76, 128.09, 128.31, 131.08, 132.16, 145.27, 147.14. Melting
point: 168–171 °C.
5.2.2.1. 1-(4-Methanesulfonylphenyl)-4-phenyl-1H-[1,2,3]tria-
zole (10a). Yield: 88%. 1H NMR (400 MHz, CDCl3): d 3.13 (s, 3H;
SO2CH3), 7.42 (m, 1H; Ar-H), 7.49 (m, 2H; Ar-H), 7.93 (d,
J = 7.8 Hz, 2H; Ar-H), 8.07 (d, J = 8.6 Hz, 2H; Ar-H), 8.16 (d,
J = 8.6 Hz, 2H; Ar-H), 8.29 (s, 1H). 13C NMR (100 MHz, CDCl3): d
43.33, 119.82, 120.23, 125.28, 127.46, 128.39, 128.97, 129.03,
129.76, 140.27, 147.59. Melting point: 250–253 °C.
5.2.3.2. 1-(4-Methanesulfonyl-phenyl)-5-p-tolyl-1H-[1,2,3]tria-
zole (11b). Yield: 11%. 1H NMR (400 MHz, CDCl3): d 2.39 (s, 3H;
CH3), 3.10 (s, 3H; SO2CH3), 7.00 (d, J = 7.8 Hz, 2H; Ar-H), 7.20 (d,
J = 7.8 Hz, 2H; Ar-H), 7.60 (d, J = 8.6 Hz, 2H; Ar-H), 7.84 (s, 1H),
8.01 (d, J = 8.6 Hz, 2H; Ar-H). 13C NMR (100 MHz, CDCl3): d 20.89,
44.30, 121.71, 125.33, 127.78, 129.19, 129.41, 130.09, 132.06,
145.47, 147.11. Melting point: 136–138 °C.
5.2.2.2. 1-(4-Methanesulfonyl-phenyl)-4-p-tolyl-1H-[1,2,3]tria-
zole (10b). Yield: 85%. 1H NMR (400 MHz, CDCl3): d 2.41 (s, 3H;
CH3), 3.18 (s, 3H; SO2CH3), 7.29 (d, J = 7.8 Hz, 2H; Ar-H), 7.81 (d,
J = 7.8 Hz, 2H; Ar-H), 8.06 (d, J = 8.6 Hz, 2H; Ar-H), 8.15 (d,
J = 8.6 Hz, 2H; Ar-H), 8.24 (s, 1H). 13C NMR (100 MHz, CDCl3): d
20.78, 43.31, 120.17, 125.19, 125.22, 129.02, 129.52, 137.38,
139.61, 143.67, 159.15. Melting point: 298–301 °C.
5.2.3.3.
5-(4-Methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-
1H-1,2,3-triazole (11c). Yield: 16%. 1H NMR (400 MHz, CDCl3): d
3.10 (s, 3H; SO2CH3), 3.83 (s, 3H; OCH3), 6.91 (d, J = 8.6 Hz, 2H;
Ar-H), 7.14 (d, J = 8.6 Hz, 2H; Ar-H), 7.60 (d, J = 8.6 Hz, 2H; Ar-H),
7.81 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H; Ar-H)). 13C NMR (100 MHz,
CDCl3): d 44.38, 55.40, 114.78, 121.72, 124.19, 125.27, 127.87,
128.12, 132.09, 145.32, 147.11, 157.33. Melting point: 154–156 °C.
5.2.2.3.
1-(4-Methanesulfonyl-phenyl)-4-(4-methoxyphenyl)-
1H-[1,2,3]triazole (10c). Yield: 82%. 1H NMR (400 MHz, CDCl3):
d 3.13 (s, 3H; SO2CH3), 3.87 (s, 3H; OCH3), 7.01 (d, J = 8.6 Hz, 2H;
Ar-H), 7.85 (d, J = 8.6 Hz, 2H; Ar-H), 8.05 (d, J = 8.6 Hz, 2H; Ar-H),
8.15 (d, J = 8.6 Hz, 2H; Ar-H), 8.20 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 43.31, 55.10, 114.38, 118.72, 120.10, 122.37, 126.67,
129.00, 140.12, 142.34, 146.01, 159.33. Melting point: 296-300 °C.
5.2.3.4.
N,N-dimethyl-4-(1-(4-(methylsulfonyl)phenyl)-1H-
[1,2,3]triazol-5-yl)aniline (11d). Yield: 27%. 1H NMR (400 MHz,
CDCl3): d 3.00 (s, 6H; N(CH3)2), 3.10 (s, 3H; SO2CH3), 6.65 (d,
J = 8.6 Hz, 2H; Ar-H), 7.06 (d, J = 8.6 Hz, 2H; Ar-H), 7.64 (d,
J = 8.6 Hz, 2H; Ar-H), 7.78 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H; Ar-H).
13C NMR (100 MHz, CDCl3):
d 39.99, 44.32, 112.42, 118.17,
121.57, 124.14, 125.29, 127.56, 132.01, 145.16, 147.09, 147.66.
Melting point: 193–195 °C.
5.2.2.4.
{4-[1-(4-Methanesulfonylphenyl)-1H-[1,2,3]triazol-4-
yl]-phenyl}-dimethylamine (10d). Yield: 80%. 1H NMR
(400 MHz, CDCl3): d 3.03 (s, 6H; N(CH3)2), 3.12 (s, 3H; SO2CH3),
6.80 (d, J = 8.6 Hz, 2H; Ar-H), 7.79 (d, J = 8.6 Hz, 2H; Ar-H), 8.05
(d, J = 8.6 Hz, 2H; Ar-H), 8.14 (d, J = 8.6 Hz, 2H; Ar-H), 8.13 (s,
1H). 13C NMR (100 MHz, CDCl3): d 39.86, 43.35, 112.22, 117.57,
119.97, 126.34, 128.99, 131.56, 136.76, 149.06, 151.10. Melting
point: 283–286 °C.
5.2.3.5. 5-(4-Chlorophenyl)-1-(4-methanesulfonylphenyl)-1H-
[1,2,3]triazole (11e). Yield: 10%. 1H NMR (400 MHz, CDCl3): d
3.11 (s, 3H; SO2CH3), 7.17 (d, J = 8.6 Hz, 2H; Ar-H), 7.39 (d,
J = 8.6 Hz, 2H; Ar-H), 8.59 (d, J = 8.6 Hz, 2H; Ar-H), 7.88 (s, 1H),
8.04 (d, J = 8.6 Hz, 2H; Ar-H). 13C NMR (100 MHz, CDCl3): d 44.32,
121.29, 125.18, 126.69, 127.82, 127.92, 130.18, 131.25, 132.04,
145.29, 147.11. Melting point: 171–172 °C.
5.2.2.5. 4-(4-Chlorophenyl)-1-(4-methanesulfonylphenyl)-1H-
[1,2,3]triazole (10e). Yield: 83%. 1H NMR (400 MHz, CDCl3): d
3.13 (s, 3H; SO2CH3), 7.46 (d, J = 8.6 Hz, 2H; Ar-H), 7.86 (d,
J = 8.6 Hz, 2H; Ar-H), 8.05 (d, J = 8.6 Hz, 2H; Ar-H), 8.16 (d,
J = 8.6 Hz, 2H; Ar-H), 8.28 (s, 1H). 13C NMR (100 MHz, CDCl3): d
43.32, 120.22, 120.29, 126.98, 128.69, 129.06, 129.08, 132.85,
139.74, 140.37, 146.39. Melting point: 253–255 °C.
5.2.3.6. 5-(4-Fluorophenyl)-1-(4-methanesulfonylphenyl)-1H-
[1,2,3]triazole (11f). Yield: 15%. 1H NMR (400 MHz, CDCl3): d 3.10
(s, 3H; SO2CH3), 7.11 (m, 2H; Ar-H), 7.22 (m, 2H, Ar-H), 7.58 (d,
J = 8.6 Hz, 2H; Ar-H), 7.86 (s, 1H), 8.02 (d, J = 8.6 Hz, 2H; Ar-H). 13C
NMR (100 MHz, CDCl3): d 44.91, 115.83 (d, JC–F = 23.2 Hz), 121.52,
126.22 (d, JC–F = 3.8 Hz), 127.25 (d, JC–F = 8.6 Hz), 127.62, 132.11,
144.99, 147.21, 159.73 (d, JC–F = 254.2 Hz). Melting point: 180–
182 °C.
5.2.2.6. 4-(4-Fluorophenyl)-1-(4-methanesulfonylphenyl)-1H-
[1,2,3]triazole (10f). Yield: 79%. 1H NMR (400 MHz, CDCl3): d
3.13 (s, 3H; SO2CH3), 7.18 (m, 2H; Ar-H), 7.90 (m, 2H, Ar-H), 8.06
(d, J = 8.6 Hz, 2H; Ar-H), 8.16 (d, J = 8.6 Hz, 2H; Ar-H), 8.25 (s,
5.3. In vitro cyclooxygenase inhibition assays
1H). 13C NMR (100 MHz, CDCl3):
d
43.31, 115.93 (d,
The ability of compound 6 and 1,2,3,-triazoles 10a–f and 11a–f
to inhibit COX-1 and COX-2 isoenzymes (IC50 values,
lM) was
JC–F = 22.9 Hz), 119.74, 120.22, 126.31 (d, JC–F = 3.9 Hz), 127.35 (d,

F. Wuest et al. / Bioorg. Med. Chem. 17 (2009) 1146–1151
1151
10. Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.; Sharpless, K. B.; Fokin,
V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998.
11. Wuest, F.; Höhne, A.; Metz, P. Org. Biomol. Chem. 2005, 3, 503.
12. Wuest, F.; Kniess, T.; Bergmann, R.; Pietzsch, J. P. Bioorg. Med. Chem. 2008, 16,
7662.
determined using an enzyme immunoassay (EIA) kit (Catalog No.
560101, Cayman Chemical, Ann Arbor, MI USA) according to a pre-
viously published method.16
13. Das, J.; Patil, S. N.; Awasthi, R.; Narasimhulu, C. P.; Trehan, S. Synthesis 2005, 11,
1801.
References and notes
14. Talley, J. Prog. Med. Chem. 1999, 36, 201.
15. Zarghi, A.; Kakhgi, S.; Hadipoor, A.; Daraee, B.; Dadrass, O. G.; Hedayati, M.
Bioorg. Med. Chem. Lett. 2008, 18, 1336.
16. Uddin, M. J.; Praveen Rao, P. N.; Knaus, E. E. Bioorg. Med. Chem. 2004, 12, 5929.
17. Chowdhury, M. A.; Dong, Y.; Chen, Q. H.; Abdellatif, K. R.; Knaus, E. E. Bioorg.
Med. Chem. 2008, 16, 1948.
18. Portevin, B.; Tordjman, C.; Pastoureau, P.; Bonnet, J.; De Nanteuil, G. J. Med.
Chem. 2000, 43, 4582.
1. Kurumbail, R. G.; Kiefer, J. R.; Marnett, L. J. Curr. Opin. Struct. Biol. 2001, 11, 752.
2. Marnett, L. J. Curr. Opin. Chem. Biol. 2000, 4, 545.
3. Fitzpatrick, F. A. Curr. Pharm. Des. 2004, 10, 577.
4. Warner, T. D.; Mitchell, J. A. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 13371.
5. Xu, X. C. Anticancer Drugs 2002, 13, 127.
6. Jiménez, P.; García, A.; Santander, S.; Piazuelo, E. Curr. Pharm. Des. 2007, 13,
2261.
7. Singh, P.; Mittal, A. Mini Rev. Med. Chem. 2008, 8, 73.
8. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128.
9. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.
19. 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.; Koboldt, C. M., et al J. Med. Chem.
1995, 38, 4570.
20. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.