Synthesis and biological evaluation of 2-phenylpyran-4-ones: A new class of orally active cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1021/jm049882t

A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.

Full text of DOI:10.1021/jm049882t

3874
J . Med. Chem. 2004, 47, 3874-3886
Syn th esis a n d Biologica l Eva lu a tion of 2-P h en ylp yr a n -4-on es: A New Cla ss of
Or a lly Active Cyclooxygen a se-2 In h ibitor s
Francisco Caturla, J uan-Miguel J ime´nez, Nu´ria Godessart, Merce` Amat, Alvaro Ca´rdenas, L´ıdia Soca,
J ordi Beleta, Hamish Ryder, and Mar´ıa I. Crespo*
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain
Received February 9, 2004
A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit
cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out
within this series, and a number of potent and selective COX-2 inhibitors were identified.
Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2
inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both
the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones
exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory
activity of these compounds was confirmed with the evaluation of their antiarthritic and
analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a
once a day administration by oral route in humans. Within this novel series, compounds 21,
31, 34, and 35 have been selected for further preclinical and clinical evaluation.
In tr od u ction
The discovery and characterization of the cyclooxy-
genase-2 (COX-2) enzyme early in the 1990s1 led to the
hypothesis that selective inhibitors of this isoform would
exhibit similar clinical efficacy but reduced ulceroge-
nicity than traditional nonsteroidal antiinflammatory
drugs (NSAIDs), which were nonselective COX-1 and
COX-2 inhibitors. Less than a decade after the COX-2
finding, celecoxib2 (Celebrex, Pfizer) and rofecoxib3
(Vioxx, Merck) (Figure 1) were launched, inaugurating
a new class of antiinflammatory agents, the coxibs. The
extensive clinical data published to date support both
the efficacy of these drugs in the management of pain
and inflammation4,5 and their improved ulcerogenic
profile.6
The potential therapeutic applications of coxibs have
been expanded beyond the areas of analgesia and
inflammation. In recent years, studies on COX-2 have
been mainly focused on cancer and neurodegenerative
disorders. The first results came from studies using
mouse models of colon cancer7 and suggested that
COX-2 could be a useful target for the prevention and
treatment of this devastating disease. In 1999, celecoxib
was approved as an adjunctive therapy for familial
adenomatous polyposis (FAP), an inherited form of
colorectal cancer. In vitro studies with human cell
cancer lines and in vivo experiments with rodents
suggest that COX-2 inhibitors may also be useful for
the treatment of other epithelial cancers from breast,
prostate, bladder, lung, and pancreas.8-10 In the field
of neurodegenerative disorders, preliminary studies
suggest a role for COX-2 in Parkinson’s disease11
whereas results on Alzheimer’s disease did not fulfill
the initial expectations.12 The concern about the poten-
tial increased risk of cardiovascular events associated
F igu r e 1. Structures of some selective COX-2 inhibitors.
with coxibs still remains to be clarified and will deter-
mine the future applications of these compounds.
In the past 5 years, three new compounds were
evaluated in clinical trials: valdecoxib13 (Bextra, Pfizer),
etoricoxib14(Arcoxia, Merck), and lumiracoxib15 (Prexige,
Novartis) (Figure 1). The second-generation COX-2
inhibitors were more selective for COX-2 over COX-1
compared to celecoxib and rofecoxib. Nevertheless, they
display an overall pharmacological profile similar to the
profile of first-generation coxibs. In this paper, we report
the characterization of a new coxib series, the 2-phen-
ylpyran-4-ones, a family of orally active, potent, and
very selective COX-2 inhibitors with one of the best
antiinflammatory profiles reported in animal models.
Ch em istr y
The general synthetic strategy employed to prepare
the 2-phenylpyran-4-one derivatives was based on a
cyclodehydration reaction of phenacyl derivatives using
PPA in AcOH. As shown in Scheme 1, a series of 2-(4-
* To whom correspondence should be addressed. Phone: (+)
34932913586. Fax: (+) 34932913420. E-mail: macrespo@almirall.es.
10.1021/jm049882t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/17/2004

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3875
Sch em e 1a
a
Reagents: (a) AlCl3, CH2Cl2; (b) MMPP, CH2Cl2/MeOH; (c) PPA, AcOH, 140 °C.
Sch em e 2a
a
Reagents: (a) AlCl3, CS2; (b) MMPP, CH2Cl2/MeOH; (c) PPA, AcOH, 140 °C.
Sch em e 3a
a
Reagents: (a) BnCl, K2CO3, acetone; (b) (i) NaOH, EtOH; (ii) SOCl2, CH3NHOCH3, Et3N; (c) RbPhCH2MgCl, THF; (d) PPA, AcOH,
140 °C; (e) H2SO4(conc).
methanesulfonylphenyl)pyran-4-one derivatives 1-16
were prepared from the corresponding phenacyl deriva-
tives 64-79 by heating in a mixture of PPA in AcOH
at 140 °C. The phenacyl derivatives 64-79 were pre-
pared from (methylthio)benzene via Friedel-Craft reac-
tion with the corresponding acyl chlorides, followed by
oxidation of the thioethers to the sulfones using mag-
nesium monoperoxiphthalate. The synthesis of the
isomer 3-(4-methanesulfonylphenyl)pyran-4-one 17
(Scheme 2) was achieved by the same cyclodehydration
reaction procedure using PPA in AcOH, starting from
the phenacyl compound 81. Compound 81 was available
through a Friedel-Crafts reaction and oxidation se-
quence starting from fluorobenzene and [4-(methylthio)-
phenyl]acetyl chloride.
4-(aminosulfonyl)benzoate in five steps, comprising the
protection of the sulfonamide to the dibenzylsulfon-
amide 83, formation of the Weinreb amide 85, Grignard
reaction with the corresponding benzylmagnesium ha-
lides, followed by cyclization with PPA/AcOH, and
finally, deprotection to the primary sulfonamide.
Scheme 4 outlines the preparation of 2-(4-methane-
sulfonylphenyl)-3-phenoxypyran-4-ones 20-47. Alkyla-
tion of the diversely substituted phenols with 2-bromo-
1-(4-methanesulfonylphenyl)ethanone16 in the presence
of potassium carbonate and tetrabutylammonium hy-
drogen sulfate in a mixture of dichloromethane/water
yielded the intermediates 88-108. These intermediates
were oxidized with magnesium monoperoxiphthalate to
the corresponding sulfones 109-129. These sulfones
were subjected to cyclodehydration to yield compounds
20-40. It is worthy to note that the substitution on the
phenol ring is very important in the final cyclization
step. Electron-withdrawing groups are well tolerated,
but electron-donating groups produce a significant
The sulfonamide derivatives 18 and 19 were obtained
from the corresponding phenacylsulfonamide intermedi-
ates 86 and 87 via the same cyclodehydration procedure
described above (see Scheme 3). Compounds 86 and 87
were obtained from the commercially available ethyl

3876 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
Sch em e 4a
a
Reagents: (a) K2CO3, tetrabutylammonium hydrogen sulfate, CH2Cl2/H2O; (b) MMPP, CH2Cl2/MeOH; (c) PPA, AcOH, 120 °C; or
PPA, Ac2O, 100 °C; (d) functional group transformations (see Experimental Section).
Ta ble 1. 2,3-Diarylpyran-4-ones as Cyclooxygenase Inhibitors:
p-Methylsulfone versus p-Sulfonamide Derivatives
Ta ble 2. 3-Phenylpyran-4-ones as Cyclooxygenase Inhibitors
a
Data are indicated as IC50 (µM). n.t.: not tested.
decrease in the final step yield. With that in mind,
compounds 41-47, which contain substituents such as
amino or methyl groups, were prepared by conventional
functional group transformations.
a
b
Data are indicated as IC50 (µM). Data are indicated as ED50
(mg/kg) using four doses (six to eight animals per group) or
percentage of inhibition (in parentheses) at 10 mg/kg (six to seven
animals). Since SEM values never exceeded 15% of the media, they
have been omitted. n.t.: not tested.
Biology
All compounds described herein were tested for their
ability to inhibit human COX-1 and COX-2 using the
whole blood assay described by Patrignani et al.17 Potent
and selective COX-2 inhibitors were evaluated in vivo
in the yeast-induced pyresis model in rat. Compounds
showing good oral activity in this model were then
tested in an assay of inflammatory pain (Atkinson
hyperalgesia model) and in a chronic model of inflam-
mation (adjuvant-induced arthritis). The pharmacoki-
netic profile of a selected group of compounds was also
evaluated in the rat.
good inhibitory activity in the HWB COX-2 assay
(compounds 18 and 19).18 So taking into account this
structural restriction, we initiated the structure-activ-
ity relationship work using 2-(4-methanesulfonylphen-
yl)pyran-4-one as a template, maintaining a methyl
group at position 6 while exploring different modifica-
tions at position 3.
Our starting point was the 2-phenylpyran-4-one
series. Most of the explored substituents showed com-
parable activities in the COX-2 assay and excellent
COX-1/COX-2 selectivity (Table 2). The 2- and 4-fluoro
derivatives (compounds 2 and 4, respectively) were
slightly more potent than compound 3 (3-fluoro) and
were both inactive in the pyresis assay. Other halogen
substitutions, such as 4-chloro (compound 5) or 4-bromo
(compound 6), slightly decrease the COX-2 activity
compared to that of compound 4 but dramatically
increased the in vivo activity. Combinations of halogen
atoms at the 3-phenyl ring also produced active com-
pounds. The most interesting one was compound 9 (3,4-
Resu lts a n d Discu ssion
Str u ctu r e-Activity Rela tion sh ip . In the diaryl
heterocyclic class of COX-2 inhibitors, it has been well
established that a p-methylsulfone or sulfonamide on
one of the phenyl groups is a requirement for good
COX-2 potency and selectivity.2,3,13,14,16 In the 2,3-
diarylpyran-4-one series, we found that only compounds
with the p-methylsulfone substitution on the 2-phenyl
ring were active (see Table 1, compounds 1 and 4 vs
17). Surprisingly, sulfonamide derivatives did not show

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3877
Ta ble 4. 3-Phenoxypyran-4-ones as Cyclooxygenase Inhibitors
Ta ble 3. 3-Substituted Pyran-4-ones as Cyclooxygenase
Inhibitors
a
b
Data are indicated as IC50 (µM). Data are indicated as ED50
(mg/kg) using four doses (six to eight animals per group) or
percentage of inhibition (in parentheses) at 10 mg/kg (six to seven
animals). Since SEM values never exceeded 15% of the media, they
have been omitted. n.t.: not tested.
dichloro), with a COX-2 activity comparable to the
activity of the reference compounds rofecoxib and etori-
coxib and with a 54-fold COX-2 selectivity. Furthermore,
it was the most active compound in the pyresis model.
In summary, the substituted 3-phenylpyran-4-one
series has been identified as a promising new class of
COX-2 inhibitors. However, these compounds were less
active, both in vitro and in vivo, than the reference
compounds rofecoxib and etoricoxib. To improve their
activity, synthetic efforts were focused on the explora-
tion of new substituents preferably at position 3 (Table
3). In this sense, several substituents were introduced
at this position, such as other aromatic rings (com-
pounds 12 and 13), an alkyl group (compound 14), a
cycloalkyl group (compound 15), and a benzyl group
(compound 16). Only compound 15 showed a COX-2
activity and selectivity similar to those of the previous
analogues but with a lack of in vivo activity in the
pyresis assay. Last, we found that the introduction of a
4-fluorophenoxy substituent at position 3 (compound 20)
was a good choice to achieve the best balance between
both in vitro and in vivo activities. Thus, compound 20
became the lead compound of a new series, the 3-phe-
noxypyran-4-ones.
Within the 3-phenoxypyran-4-one derivatives (Table
4), the presence of halogen atoms in the para position
of the 3-phenoxy ring generally enhanced the COX-2
activity with respect to the unsubstituted analogue 41
(compounds 21, 24, and 25). All these halogenated
compounds showed very good COX-1/COX-2 selectivity,
especially the p-chloro derivative 21, which is the most
selective compound of this series. The 2- and 4-methyl
derivatives (compounds 42 and 44, respectively) were
around 7-fold more potent than compound 43 (3-methyl
substituted). Compound 46 with a p-amino group was
less potent than the previous analogues (i.e., compounds
20, 21, 24, 25, and 44) but was quite selective for COX-
a
b
Data are indicated as IC50 (µM). Data are indicated as ED50
(mg/kg) using four doses (six to eight animals per group) or
percentage of inhibition (in parentheses) at 10 mg/kg (six to seven
animals). Since SEM values never exceeded 15% of the media, they
have been omitted. n.t.: not tested.
2. Compounds 26 and 28, with 4-trifluoromethyl and
4-trifluoromethoxy groups, respectively, showed a de-
crease in COX-2 potency but still retained good selectiv-
ity. Other para monosubstituted derivatives with elec-
tron-withdrawing groups (27, 29, 30, and 47) were
inactive as COX-2 inhibitors. The oral testing of a subset
of monosubstituted phenoxy derivatives revealed that
only compounds 20 and 21 were active in the pyresis
assay. With regard to the disubstituted derivatives,
several combinations of halogen atoms, methyl groups,
and methoxy groups were also tested. Some of them
were very potent at inhibiting the COX-2 assay and also
very selective (compounds 31, 34-40, and 45). Indeed,
compounds 31 and 45 were the most active compounds
of this series, having a COX-2 activity in the nanomolar
range. Moreover, the in vivo activity in the pyresis assay
was clearly improved for compounds 31 and 34.
In conclusion, within the 2-phenylpyran-4-one series,
we have identified potent and selective COX-2 inhibitors
with promising preliminary in vivo activity.

3878 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
Ta ble 5. In Vivo Pharmacological Profile of Selected
Pyran-4-ones
effects support the clinical development of these com-
pounds in inflammation and pain. The evaluation of the
3-phenoxypyran-4-ones in animal models of cancer and
neurodegenerative disorders is in progress.
Con clu sion s
We have identified the 2-phenylpyran-4-ones as a
novel series of highly potent and selective COX-2
inhibitors and demonstrated that the p-methylsulfone
group at the 2-phenyl ring gives the best COX-2 inhibi-
tory activity. Of all the substituents introduced on the
pyranone, the 3-aryloxy provided the most interesting
compounds in terms of in vitro and in vivo activity. A
further enhancement in activity was observed with
halogen-substituted 3-aryloxypyranones, with activities
in the nanomolar range. A selected group of 3-phenoxy-
pyran-4-ones exhibited excellent oral activity when
tested in assays of chronic inflammation, fever, and
pain. Moreover, the good pharmacokinetic profile in rats
of a selected group of 3-phenoxypyran-4-ones may be
compatible with a once a day oral administration in
humans. Furthermore, these compounds were devoid of
gastrointestinal toxicity at high doses. Within this
pyranone class, the 3-phenoxypyran-4-ones represent an
improvement not only in the COX-2 potency and selec-
tivity but also in the oral biological activity. To our
knowledge, some of these compounds display some of
the best antiarthritic activities reported in animal
models. On the basis of their in vivo profile and lack of
gastrointestinal toxicity, compounds 21, 31, 34, and 35
have been selected for further preclinical and clinical
evaluation. Results of these studies will be reported in
due course.
a
Data are indicated as ED50 (mg/kg) using four doses (six to
b
eight animals per group). Data are indicated as percentage of
inhibition at 3 mg/kg ( SEM (six to seven animals).
Ta ble 6. Pharmacokinetic Profile of Selected
3-Phenoxypyran-4-ones after Oral Administratrion of 10 mg/kg
a
Data (µg/mL) are obtained using three animals per group.
b
Data (µg‚h/mL) are obtained using three animals per group.
c Data (h) are obtained using three animals per group.
In Vivo Activity. Selected compounds were evalu-
ated in the adjuvant-induced arthritis model and the
Atkinson hyperalgesia assay (Table 5). In the 3-phen-
ylpyran-4-one series, only compound 9 showed good
activity in vivo, with a potency in both assays similar
to the potency of rofecoxib and etoricoxib. Unfortunately,
this compound was hepatotoxic in rat (data not shown),
and further characterization of this series was discon-
tinued.
In the 3-phenoxypyran-4-one series, compounds not
only displayed a high potency and selectivity for COX-2
in vitro but also showed good oral activity in vivo. In
the Atkinson assay, this series showed an efficacy
comparable to the efficacy of reference compounds.
However, in the model of chronic inflammation, com-
pounds 31, 34, and 35 exhibited excellent activity, with
potencies from 35- to 50-fold higher than the potencies
of rofecoxib and etoricoxib.
Some of the 3-phenoxypyran-4-ones (21, 31, 34, and
35) were selected for pharmacokinetic studies. Although
compounds 21 and 31 showed a better pharmacokinetic
profile than compounds 34 and 35, the four compounds
exhibited a similar in vivo activity possibly because of
differences in protein binding (Table 6).
The evaluation of compounds 21, 31, 34 and 35 on
gastrointestinal toxicity showed that they did not cause
any ulceration or hemoglobin loss after a 4-day treat-
ment at 100 mg kg-1 day-1 (data not shown).16
In conclusion, selected 3-phenoxypyran-4-ones display
a favorable pharmacological profile relative to the
reference compounds rofecoxib and etoricoxib. Their
excellent in vivo activity and lack of gastrointestinal side
Exp er im en ta l Section
1. Biology. Gen er a l. COX-2 and COX-1 activity in human
whole blood, Atkinson hyperalgesia model in rat, adjuvant-
induced arthritis model in rat, and the yeast-induced pyresis
model in rat were performed as described previously.16 For all
the in vivo assays, male Wistar rats (Interfauna Iberica, Spain)
were used. Unless otherwise indicated, rats were fasted with
free access to water for 18 h prior to the assay. Statistic
analysis between the different treatment groups was calcu-
lated according to the analysis of variance (ANOVA) test. A
value of p < 0.05 was considered to be significant. The
appropriate animal ethics committees have approved all the
experimental protocols used in this paper.
2. P h a r m a cok in etics in Ra ts. Compounds were admin-
istered by oral route to fasted male Wistar rats. At different
time points, blood samples were obtained and the blood and
plasma content was analyzed by HPLC as described below.
Pharmacokinetic parameters were determined by noncom-
partmental analysis using WinNonlin (Pharsight, Inc., Moun-
tain View, CA).
3. HP LC An alysis for P h ar m acokin etic Stu dies. Plasma
levels (for compounds 21, 31, 34, and 35) were determined by
an isocratic HPLC (515 pump, Waters) and UV detection (λ )
270-280 nm, UV2487 Waters) method using an on-line solid-
phase system (PROSPEKT, Spark-Holland) assisted by a
sampling injector (ASPEC XL, Gilson). Briefly, 1 mL of 20 mM,
pH 4, sodium acetate buffer was added to 5 mL of disposable
conical tubes containing 100 µL of plasma (200 µL for
compound 21). The mixture was shaken for 15 s with a vortex
and centrifuged at 4000 rpm for 10 min (Megafuge 1.0R,
Heraeus). Samples were then loaded into a Gilson sample
processor. The on-line solid-phase extraction was carried out
by the PROSPEKT system connected to a Gilson sample
injector, using C2 and Oasis (for compounds 34 and 35)
cartridges (Baker and WATERS, respectively). The passage
of the fluids through the cartridges was carried out by the

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3879
ASPEC sampling injector, using the following sample prepara-
tion steps: (1) activate the cartridge with 1.5 mL of methanol
(acetonitrile for compounds 34 and 35); (2) condition the
cartridge with 1.5 mL of water; (3) load the sample; (4) wash
the sample with 3 mL of water (for compound 31), with 1 mL
of methanol/water (10:90, v/v) and 2 mL of water (for com-
pound 21), with 2 mL of water and 1 mL of methanol/water
(20:80, v/v, for compound 34), or with 2 mL of water and 1 mL
of methanol/water (60:40, v/v for compound 35). Finally the
elution from the analytical column (RP8 (for compound 21) or
C18, 150 mm × 4.6 mm, 5 µm, Symmetry, WATERS) was
carried out by passage through the cartridge mobile phase for
0.5 min at a flow rate of 1 mL/min. The mobile phase was a
mixture of acetonitrile and 20 mM sodium phosphate contain-
ing 0.2% of triethylamine (pH 7 for compound 21 and pH 3
for compound 31) or 10 mM sodium phosphate buffer, pH 3
(for compounds 34 and 35). The corresponding isocratic
methods were 40% of organic for compound 21, 35% of organic
for compound 31, 39% of organic for compound 34, and 41%
of organic for compound 35. With these conditions, all com-
pounds had a retention time in between 9 and 12 min.
4. Deter m in a tion of P la sm a P r otein Bin d in g (P P B).
Aliquots of 1 mL of pooled human plasma were incubated with
2.5 µg/mL of test compound at 37 °C for 2 h. Samples were
then transferred to a Centrifree micropartition device (Milli-
pore, Bedford, MA) and centrifuged at 2000g for 15 min.
Calibration standards of 25 and 250 ng/mL of each compound
in PBS were used to quantify the samples. An amount of 100
µL of the ultrafiltrate or of calibration standard was diluted
(1:1) with acetonitrile/water (50:50, v/v) and injected into the
HPLC/MS system. Protein-free compound levels were deter-
mined by an isocratic HPLC (Alliance 2790 Waters) and MS
detection (ZMD, Micromass, mode SIR) method.
5. Ch em istr y. Gen er a l. Reagents, starting materials, and
solvents were purchased from commercial suppliers and used
as received. All organic solutions were dried over sodium
sulfate. Concentration refers to evaporation under vacuum
using a Bu¨chi rotatory evaporator. Reaction products were
purified, when necessary, by flash chromatography on silica
gel (40-63 µm) with the solvent system indicated. Spectro-
scopic data were recorded on a Varian Gemini 300 spectrom-
eter. Melting points were recorded on a Bu¨chi 535 apparatus.
Where analyses are indicated only by symbols of the elements,
results obtained were within 0.4% of the theoretical values.
The chromatographic separations were obtained using a
Waters 2795 system equipped with a Symmetry C18 (2.1 mm
× 100 mm, 3.5 µm) column. The mobile phase was formic acid
(0.46 mL), ammonia (0.115 mL), and water (1000 mL) (solution
A) and formic acid (0.4 mL), ammonia (0.1 mL), methanol (500
mL), and acetonitrile (500 mL) (solution B): initially from 0%
to 95% of solution B in 20 min and then 4 min with 95% of
solution B. The reequilibration time between two injections
was 5 min. The flow rate was 0.4 mL/min. The injection volume
was 5 µL. Also, a Kromasil C18 (4.61 × 100 mm, 5 µm) column
was used. The mobile phase was 0.01 M phosphoric acid, 1 N
sodium hydroxyde at pH 3 (A) and acetonitrile (B): initially
from 0% to 83% of B in 55 min and then 15 min with 83% of
B. The reequilibration time between two injections was 5 min.
The flow rate was 1 mL/min. The injection volume was 10 µL.
Diode array chromatograms were processed at 210 nm.
5.1. Syn th esis of P yr on es 1-16 (Sch em e 1). Gen er a l
P r oced u r e for th e Syn th esis of In ter m ed ia tes 48-63.
Met h od A. 1-(4-Met h ylsu lfa n ylp h en yl)-2-p h en ylet h a -
n on e (48). To a cooled solution of 7.30 g (58.8 mmol) of
thioanisole and 10.2 g (76.5 mmol) of aluminum trichloride in
90 mL of dry CH2Cl2 was added dropwise a solution of 10.0 g
(64.7 mmol) of phenylacetyl chloride in 20 mL of dry CH2Cl2.
The mixture was stirred at room temperature for 2.5 h and
poured into 6 N HCl/ice. The aqueous layer was separated and
extracted with CH2Cl2. The combined organic phase was
washed with saturated NaHCO3, dried, and evaporated. The
resulting solid was crystallized from ethyl ether to give 14.4 g
(92%) of the title compound: 1H NMR (CDCl3) δ 2.52 (s, 3H),
4.24 (s, 2H), 7.20-7.35 (m, 7H), 7.92 (d, J ) 8.5 Hz, 2H).
2-(2-F lu or op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (49) was prepared according to method A starting from
thioanisole (3.33 g) and 2-fluorophenylacetyl chloride. Crystal-
lization from ethyl ether gave 3.99 g (57%) of 49: 1H NMR
(CDCl3) δ 2.52 (s, 3H), 4.29 (s, 2H), 7.03-7.14 (m, 2H), 7.21-
7.31 (m, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.94 (d, J ) 8.5 Hz,
2H).
2-(3-F lu or op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (50) was prepared according to method A starting from
thioanisole (3.80 g) and 3-fluorophenylacetyl chloride. Crystal-
lization from hexane gave 1.39 g (16%) of 50: 1H NMR (CDCl3)
δ 2.56 (s, 3H), 4.24 (s, 2H), 6.93-7.04 (m, 3H), 7.25-7.33 (m,
1H), 7.28 (d, J ) 8.5 Hz, 2H), 7.95 (d, J ) 8.5 Hz, 2H).
2-(4-F lu or op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (51) was prepared according to method A starting from
thioanisole (23.5 g) and 4-fluorophenylacetyl chloride. Crystal-
lization from hexane gave 38.0 g (77%) of 51: 1H NMR (CDCl3)
δ 2.52 (s, 3H), 4.21 (s, 2H), 6.97-7.04 (m, 2H), 7.18-7.28 (m,
2H), 7.26 (d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Ch lor op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (52) was prepared according to method A starting from
thioanisole (6.18 g) and 4-chlorophenylacetyl chloride. Crystal-
lization from ethyl ether gave 10.7 g (78%) of 52: 1H NMR
(CDCl3) δ 2.52 (s, 3H), 4.20 (s, 2H), 7.20 (d, J ) 8.5 Hz, 2H),
7.26 (d, J ) 8.5 Hz, 2H), 7.29 (d, J ) 8.5 Hz, 2H), 7.90 (d, J )
8.5 Hz, 2H).
2-(4-Br om op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (53) was prepared according to method A starting from
thioanisole (5.25 g) and 4-bromophenylacetyl chloride. Crystal-
lization from ethyl ether gave 14.0 g (93%) of 53: 1H NMR
(CDCl3) δ 2.52 (s, 3H), 4.20 (s, 2H), 7.11 (d, J ) 8.5 Hz, 2H),
7.25 (d, J ) 8.5 Hz, 2H), 7.44 (d, J ) 8.5 Hz, 2H), 7.90 (d, J )
8.5 Hz, 2H).
1-(4-Meth ylsu lfan ylph en yl)-2-(4-tr iflu or om eth ylph en yl)-
eth a n on e (54) was prepared according to method A starting
from thioanisole (9.62 g) and 4-trifluoromethylphenylacetyl
chloride. Purification by flash chromatography, eluting with
EtOAc/hexane (1:6), gave 1.86 g (8%) of 54: 1H NMR (CDCl3)
δ 2.54 (s, 3H), 4.33 (s, 2H), 7.28 (d, J ) 8.5 Hz, 2H), 7.39 (d, J
) 8.5 Hz, 2H), 7.60 (d, J ) 8.5 Hz, 2H), 7.94 (d, J ) 8.5 Hz,
2H).
2-(4-Met h ylp h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (55) was prepared according to method A starting from
thioanisole (23.0 g) and 4-methylphenylacetyl chloride. Crys-
tallization from EtOAc/hexane gave 33.1 g (66%) of 55: 1H
NMR (CDCl3) δ 2.33 (s, 3H), 2.52 (s, 3H), 4.20 (s, 2H), 7.14 (s,
4H), 7.25 (d, J ) 8.5 Hz, 2H), 7.94 (d, J ) 8.5 Hz, 2H).
2-(3,4-Dich lor op h en yl)-1-(4-m et h ylsu lfa n ylp h en yl)-
eth a n on e (56) was prepared according to method A starting
from thioanisole (14.0 g) and 3,4-dichlorophenylacetyl chloride.
Crystallization from ethyl ether gave 28.0 g (72%) of 56: 1H
NMR (CDCl3) δ 2.52 (s, 3H), 4.20 (s, 2H), 7.10 (d, J ) 8.5 Hz,
1H), 7.27 (d, J ) 8.5 Hz, 2H), 7.37 (d, J ) 8.5 Hz, 1H), 7.40 (s,
1H), 7.92 (d, J ) 8.5 Hz, 2H).
2-(2,4-Diflu or op h e n yl)-1-(4-m e t h ylsu lfa n ylp h e n yl)-
eth a n on e (57) was prepared according to method A starting
from thioanisole (2.85 g) and 2,4-difluorophenylacetyl chloride.
Crystallization from ethyl ether gave 5.10 g (80%) of 57: 1H
NMR (CDCl3) δ 2.52 (s, 3H), 4.24 (s, 2H), 6.80-6.89 (m, 2H),
7.15-7.23 (m, 1H), 7.27 (d, J ) 8.5 Hz, 2H), 7.93 (d, J ) 8.5
Hz, 2H).
2-(4-Ch lor o-2-flu or oph en yl)-1-(4-m eth ylsu lfan ylph en yl)-
eth a n on e (58) was prepared according to method A starting
from thioanisole (3.03 g) and 2-chloro-4-fluorophenylacetyl
chloride. Crystallization from ethyl ether gave 5.20 g (72%) of
58: 1H NMR (CDCl3) δ 2.52 (s, 3H), 4.24 (s, 2H), 7.10-7.17
(m, 3H), 7.27 (d, J ) 8.5 Hz, 2H), 7.92 (d, J ) 8.5 Hz, 2H).
2-(2-Naph th yl)-1-(4-m eth ylsu lfan ylph en yl)eth an on e (59)
was prepared according to method A starting from thioanisole
(6.10 g) and 2-naphthylacetyl chloride. Crystallization from
1
ethyl ether gave 12.9 g (90%) of 59: H NMR (CDCl3) δ 2.52
(s, 3H), 4.40 (s, 2H), 7.27-7.52 (m, 6H), 7.73 (s, 1H), 7.82 (d,
J ) 8.5 Hz, 2H), 7.94 (d, J ) 8.5 Hz, 2H).
1-(4-Meth ylsu lfa n ylp h en yl)-2-(5,6,7,8-tetr a h yd r on a p h -
th a len -2-yl)eth a n on e (60) was prepared according to method
A starting from thioanisole (2.42 g) and (5,6,7,8-tetrahy-
dronaphthalen-2-yl)acetyl chloride.19 The title compound was
obtained as a brown oil that was used in the next step without

3880 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
further purification. 1H NMR (CDCl3) δ 1.72-1.76 (m, 4H),
2.49 (s, 3H), 2.68-2.73 (m, 4H), 4.13 (s, 2H), 6.88-6.97 (m,
3H), 7.21 (d, J ) 8.5 Hz, 2H), 7.85 (d, J ) 8.5 Hz, 2H).
3-Meth yl-1-(4-m eth ylsu lfa n ylp h en yl)bu ta n -1-on e (61)
was prepared according to method A starting from thioanisole
(5.25 g) and isobutyryl chloride. Crystallization from isopropyl
ether gave 6.20 g (71%) of 61: 1H NMR (CDCl3) δ 1.00 (d, J )
6.3 Hz, 6H), 2.24-2.33 (m, 1H), 2.52 (s, 3H), 2.80 (d, J ) 6.3
Hz, 2H), 7.26 (d, J ) 8.5 Hz, 2H), 7.93 (d, J ) 8.5 Hz, 2H).
2-Cycloh exyl-1-(4-m eth ylsu lfa n ylp h en yl)eth a n on e (62)
was prepared according to method A starting from thioanisole
(7.94 g) and cyclohexylacetyl chloride. Crystallization from
isopropyl ether gave 14.9 g (94%) of 62: 1H NMR (CDCl3) δ
0.95-1.33 (m, 5H), 1.65-1.76 (m, 5H), 1.87-2.00 (m, 1H), 2.52
(s, 3H), 2.79 (d, J ) 8.0 Hz, 2H), 7.25 (d, J ) 8.5 Hz, 2H), 7.85
(d, J ) 8.5 Hz, 2H).
from 56 (28.0 g). Crystallization from ethyl ether gave 16.0 g
(53%) of 72: 1H NMR (DMSO) δ 3.28 (s, 3H), 4.55 (s, 2H), 7.25
(d, J ) 8.5 Hz, 1H), 7.54 (d, J ) 8.5 Hz, 1H), 7.59 (s, 1H), 8.09
(d, J ) 8.5 Hz, 2H), 8.2 (d, J ) 8.5 Hz, 2H).
2-(2,4-Diflu or op h en yl)-1-(4-m et h a n esu lfon ylp h en yl)-
eth a n on e (73) was prepared according to method B starting
from 57 (5.33 g). Crystallization from ethyl ether gave 5.38 g
(91%) of 73: 1H NMR (CDCl3) δ 3.08 (s, 3H), 4.33 (s, 2H), 6.85-
6.92 (m, 2H), 7.15-7.23 (m, 1H), 8.07 (d, J ) 8.5 Hz, 2H), 8.19
(d, J ) 8.5 Hz, 2H).
2-(4-Ch lor o-2-flu or oph en yl)-1-(4-m eth an esu lfon ylph en -
yl)eth a n on e (74) was prepared according to method B
starting from 58 (5.20 g). Crystallization from ethyl ether gave
5.00 g (87%) of 74: 1H NMR (CDCl3) δ 3.12 (s, 3H), 4.37 (s,
2H), 7.13-7.20 (m, 3H), 8.11 (d, J ) 8.5 Hz, 2H), 8.21 (d, J )
8.5 Hz, 2H).
2-(2-N a p h t h y l)-1-(4-m e t h a n e s u lfo n y lp h e n y l)e t h a -
n on e (75) was prepared according to method B starting from
59 (12.9 g). Crystallization from ethyl ether gave 14.5 g (91%)
of 75: 1H NMR (CDCl3) δ 3.05 (s, 3H), 4.45 (s, 2H), 7.44-7.52
(m, 3H), 7.72 (s, 1H), 7.77-7.93 (m, 3H), 8.03 (d, J ) 8.5 Hz,
2H), 8.19 (d, J ) 8.5 Hz, 2H).
1-(4-Meth ylsu lfa n ylp h en yl)-3-p h en ylp r op a n -1-on e (63)
was prepared according to method A starting from thioanisole
(7.56 g) and 3-phenylpropionyl chloride. Crystallization from
ethyl ether gave 15.0 g (96%) of 63: 1H NMR (CDCl3) δ 2.52
(s, 3H), 3.07 (t, J ) 8.0 Hz, 2H), 3.25 (t, J ) 8.0 Hz, 2H), 7.20-
7.33 (m, 7H), 7.89 (d, J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of In ter m ed ia tes
64-79. Meth od B. 1-(4-Meth a n esu lfon ylp h en yl)-2-p h en -
yleth a n on e (64). To a cooled solution of 14.4 g (59.3 mmol)
of 48 in 250 mL of CH2Cl2 and 50 mL of MeOH was added
35.2 g (71.2 mmol) of magnesium monoperoxyphthalate hexahy-
drate for 30 min. The mixture was stirred at room temperature
overnight. The resulting suspension was poured into saturated
NaHCO3. The solid obtained was filtered, dried, and recrystal-
lized from EtOH to give 8.76 g (57%) of the title compound:
1H NMR (CDCl3) δ 3.08 (s, 3H), 4.30 (s, 2H), 7.25-7.38 (m,
5H), 8.07 (d, J ) 8.5 Hz, 2H), 8.17 (d, J ) 8.5 Hz, 2H).
2-(2-F lu or op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (65) was prepared according to method B starting from
49 (3.97 g). Crystallization from isopropyl ether gave 3.51 g
(79%) of 65: 1H NMR (CDCl3) δ 3.09 (s, 3H), 4.36 (s, 2H), 7.06-
7.15 (m, 2H), 7.23-7.34 (m, 2H), 8.07 (d, J ) 8.5 Hz, 2H), 8.21
(d, J ) 8.5 Hz, 2H).
2-(3-F lu or op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (66) was prepared according to method B starting from
50 (1.39 g). Crystallization from isopropyl ether gave 1.10 g
(71%) of 66: 1H NMR (CDCl3) δ 3.08 (s, 3H), 4.34 (s, 2H), 6.94-
7.03 (m, 3H), 7.22-7.35 (m, 1H), 8.07 (d, J ) 8.5 Hz, 2H), 8.19
(d, J ) 8.5 Hz, 2H).
2-(4-F lu or op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (67) was prepared according to method B starting from
51 (35.5 g). Recrystallization from isopropyl alcohol gave 25.0
g (63%) of 67: 1H NMR (CDCl3) δ 3.08 (s, 3H), 4.29 (s, 2H),
7.03 (dd, J 1 ) J F-H ) 9.0 Hz, 2H), 7.22 (dd, J 1 ) J F-H ) 9.0
Hz, 2H), 8.08 (d, J ) 8.5 Hz, 2H), 8.16 (d, J ) 8.5 Hz, 2H).
2-(4-Ch lor op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (68) was prepared according to method B starting from
52 (9.70 g). Crystallization from ethyl ether gave 7.40 g (68%)
of 68: 1H NMR (CDCl3) δ 3.09 (s, 3H), 4.31 (s, 2H), 7.20 (d, J
) 8.5 Hz, 2H), 7.33 (d, J ) 8.5 Hz, 2H), 8.05 (d, J ) 8.5 Hz,
2H), 8.16 (d, J ) 8.5 Hz, 2H).
1-(4-Meth an esu lfon ylph en yl)-2-(5,6,7,8-tetr ah ydr on aph -
th a len -2-yl)eth a n on e (76) was prepared according to method
B starting from 60 (6.10 g of crude material). The title
compound was obtained (5.90 g, 92%) as a brown oil: 1H NMR
(CDCl3) δ 1.77-1.80 (m, 4H), 2.70-2.75 (m, 4H), 3.08 (s, 3H),
4.27 (s, 2H), 6.93-7.04 (m, 3H), 8.03 (d, J ) 8.5 Hz, 2H), 8.16
(d, J ) 8.5 Hz, 2H).
3-Meth yl-1-(4-m eth an esu lfon ylph en yl)bu tan -1-on e (77)
was prepared according to method B starting from 61 (6.10
g). Crystallization from isopropyl ether gave 4.28 g (61%) of
77: 1H NMR (CDCl3) δ 1.00 (d, J ) 6.3 Hz, 6H), 2.25-2.35
(m, 1H), 2.88 (d, J ) 6.3 Hz, 2H), 3.09 (s, 3H), 8.05 (d, J ) 8.5
Hz, 2H), 8.12 (d, J ) 8.5 Hz, 2H).
2-Cycloh exyl-1-(4-m et h a n esu lfon ylp h en yl)et h a n on e
(78) was prepared according to method B starting from 62
(14.9 g). Crystallization from isopropyl ether gave 16.0 g (95%)
of 78: 1H NMR (CDCl3) δ 0.94-1.32 (m, 5H), 1.64-1.80 (m,
5H), 1.91-2.06 (m, 1H), 2.88 (d, J ) 8.0 Hz, 2H), 3.11 (s, 3H),
8.05 (d, J ) 8.5 Hz, 2H), 8.11 (d, J ) 8.5 Hz, 2H).
1-(4-Meth an esu lfon ylph en yl)-3-ph en ylpr opan -1-on e (79)
was prepared according to method B starting from 63 (15.0
g). Crystallization from ethyl ether gave 14.4 g (85%) of 79:
1H NMR (CDCl3) δ 3.07 (s, 3H), 3.08 (t, J ) 8.0 Hz, 2H), 3.36
(t, J ) 8.0 Hz, 2H), 7.20-7.33 (m, 5H), 8.03 (d, J ) 8.5 Hz,
2H), 8.11 (d, J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of P yr on es 1-16.
Meth od C. 2-(4-Meth an esu lfon ylph en yl)-6-m eth yl-3-ph en -
ylp yr a n -4-on e (1). A solution of 40.0 g of polyphosphoric acid
in 50 mL of acetic acid was heated at 140 °C. Then a
suspension of 4.00 g (14.6 mmol) of 64 in 10 mL of acetic acid
was added. The mixture was heated at 140 °C for 16 h. After
cooling, the reaction mixture was poured into ice/water and
extracted with EtOAc. The organic solution was dried, and the
solvent was removed under reduced pressure. The residual oil
was purified by flash chromatography, eluting with EtOAc/
hexane (2:1), to give 3 g of crude 1. Recrystallization from
EtOH gave 1.00 g (20%) of the title compound: mp 185 °C; 1H
NMR (DMSO) δ 2.38 (s, 3H), 3.22 (s, 3H), 6.40 (s, 1H), 7.10-
7.13 (m, 2H), 7.29-7.31 (m, 3H), 7.55 (d, J ) 8.5 Hz, 2H), 7.86
(d, J ) 8.5 Hz, 2H). HPLC purity (method 1): 99.4%. Anal.
(C19H16O4S) C, H, S.
2-(4-Br om op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (69) was prepared according to method B starting from
53 (10.0 g). Crystallization from EtOAc gave 8.50 g (70%) of
69: 1H NMR (DMSO) δ 3.30 (s, 3H), 4.50 (s, 2H), 7.26 (d, J )
8.5 Hz, 2H), 7.54 (d, J ) 8.5 Hz, 2H), 8.09 (d, J ) 8.5 Hz, 2H),
8.28 (d, J ) 8.5 Hz, 2H).
1-(4-Meth an esu lfon ylph en yl)-2-(4-tr iflu or om eth ylph en -
yl)eth a n on e (70) was prepared according to method B
starting from 54 (1.86 g). Crystallization from ethyl ether gave
1.57 g (77%) of 70: 1H NMR (CDCl3) δ 3.11 (s, 3H), 4.41 (s,
2H), 7.40 (d, J ) 8.5 Hz, 2H), 7.63 (d, J ) 8.5 Hz, 2H), 8.08 (d,
J ) 8.5 Hz, 2H), 8.19 (d, J ) 8.5 Hz, 2H).
1-(4-Meth a n esu lfon ylp h en yl)-2-(4-m eth ylp h en yl)eth a -
n on e (71) was prepared according to method B starting from
55 (7 g). Crystallization from ethyl ether gave 1.84 g (23%) of
71: 1H NMR (CDCl3) δ 2.33 (s, 3H), 3.07 (s, 3H), 4.26 (s, 2H),
7.12 (s, 4H), 8.03 (d, J ) 8.5 Hz, 2H), 8.15 (d, J ) 8.5 Hz, 2H).
2-(3,4-Dich lor op h en yl)-1-(4-m eth a n esu lfon ylp h en yl)-
eth a n on e (72) was prepared according to method B starting
3-(2-F lu or op h e n yl)-2-(4-m e t h a n e su lfon ylp h e n yl)-6-
m eth ylp yr a n -4-on e (2) was prepared according to method
C starting from 65 (3.50 g). Purification by flash chromatog-
raphy, eluting with EtOAc/hexane (2:1), gave 2.96 g (69%) of
1
2: mp 136-137 °C; H NMR (DMSO) δ 2.40 (s, 3H), 3.04 (s,
3H), 6.36 (s, 1H), 6.99-7.05 (m, 1H), 7.10-7.20 (m, 2H), 7.29-
7.37 (m, 1H), 7.52 (d, J ) 8.5 Hz, 2H), 7.84 (d, J ) 8.5 Hz,
2H). HPLC purity (method 1): 96.5%.
3-(3-Fluorophenyl)-2-(4-methanesulfonylphenyl)-6-meth-
ylp yr a n -4-on e (3) was prepared according to method C
starting from 66 (1.10 g). Purification by flash chromatogra-
phy, eluting with EtOAc/hexane (2:1), gave 0.65 g (54%) of 3:
mp 182 °C; 1H NMR (DMSO) δ 2.37 (s, 3H), 3.22 (s, 3H), 6.41

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3881
(s, 1H), 6.88 (d, J ) 7.9 Hz, 1 H), 7.03 (dt, J ) 10.0, 2.0 Hz,
1H), 7.12 (td, J ) 8.7, 2.0 Hz, 1H), 7.31 (td, J ) 7.9, 6.4 Hz,
1H), 7.58 (d, J ) 8.5 Hz, 2H), 7.88 (d, J ) 8.5 Hz, 2H). HPLC
purity (method 1): 99.3%.
6.40 (s, 1H), 7.20 (d, J ) 8.2 Hz, 1H), 7.42-7.52 (m, 4H), 7.69-
7.83 (m, 6H). HPLC purity (method 1): 95.4%.
2-(4-Met h a n esu lfon ylp h en yl)-6-m et h yl-3-(5,6,7,8-t et -
r a h yd r on a p h t h a len -2-yl)p yr a n -4-on e (13) was prepared
according to method C starting from 76 (5.90 g). Purification
by flash chromatography, eluting with EtOAc/hexane (1:1),
gave 0.48 g (8%) of 13: mp 103 °C; 1H NMR (DMSO) δ 1.63-
1.74 (m, 4H), 2.35 (s, 3H), 2.60-2.67 (m, 4H), 3.22 (s, 3H), 6.35
(s, 1H), 6.71 (d, J ) 8.0 Hz, 1H), 6.84 (s, 1H), 6.93 (d, J ) 8.0
Hz, 1H), 7.58 (d, J ) 8.5 Hz, 2H), 7.87 (d, J ) 8.2 Hz, 2H).
HPLC purity (method 1): 95.0%.
3-Isop r op yl-2-(4-m eth a n esu lfon ylp h en yl)-6-m eth ylp y-
r a n -4-on e (14) was prepared according to method C starting
from 77 (3.50 g). Purification by flash chromatography, eluting
with EtOAc/hexane (1:1), gave 0.22 g (5%) of 14: mp 108 °C;
1H NMR (DMSO) δ 1.22 (d, J ) 6.3 Hz, 6H), 2.24 (s, 3H), 2.61
(h, J ) 6.3 Hz, 1H), 3.31 (s, 3H), 6.20 (s, 1H), 7.82 (d, J ) 8.5
Hz, 2H), 8.09 (d, J ) 8.5 Hz, 2H). HPLC purity (method 1):
99.3%.
3-Cycloh exyl-2-(4-m eth an esu lfon ylph en yl)-6-m eth ylpy-
r a n -4-on e (15) was prepared according to method C starting
from 78 (16.0 g). Purification by flash chromatography, eluting
with EtOAc/hexane (3:1), gave 2.3 g (12%) of 15: mp 98-99
°C; 1H NMR (CDCl3) δ 1.02-1.35 (m, 3H), 1.46-1.75 (m, 5H),
2.25 (s, 3H), 2.16-2.38 (m, 3H), 3.14 (s, 3H), 6.13 (s, 1H), 7.66
(d, J ) 8.2 Hz, 2H), 8.08 (d, J ) 8.2 Hz, 2H). HPLC purity
(method 1): 98.6%.
3-(4-Fluorophenyl)-2-(4-methanesulfonylphenyl)-6-meth-
ylp yr a n -4-on e (4) was prepared according to method C
starting from 67 (1.00 g). Purification by flash chromatogra-
phy, eluting with EtOAc/hexane (1:1), gave 0.50 g (41%) of 4:
mp 237 °C; 1H NMR (DMSO) δ 2.37 (s, 3H), 3.22 (s, 3H), 6.39
(s, 1H), 7.13-7.16 (m, 4H), 7.56 (d, J ) 8.5 Hz, 2H), 7.88 (d, J
) 8.5 Hz, 2H). HPLC purity (method 1): 98.4%. Anal. (C19H15
FO4S) C, H, S.
-
3-(4-Chlorophenyl)-2-(4-methanesulfonylphenyl)-6-meth-
ylp yr a n -4-on e (5) was prepared according to method C
starting from 68 (2.00 g). Recrystallization from EtOH gave
1.70 g (70%) of 5: mp 182°C; 1H NMR (DMSO) δ 2.38 (s, 3H),
3.24 (s, 3H), 6.41 (s, 1H), 7.15 (d, J ) 8.5 Hz, 2H), 7.38 (d, J
) 8.5 Hz, 2H), 7.58 (d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz,
2H). HPLC purity (method 1): 98.6%. Anal. (C19H15ClO4S) C,
H, S.
3-(4-Bromophenyl)-2-(4-methanesulfonylphenyl)-6-meth-
ylp yr a n -4-on e (6) was prepared according to method C
starting from 69 (8.5 g). Purification by flash chromatography,
eluting with EtOAc/hexane (2:1), gave 1.03 g (12%) of 6: mp
1
198 °C; H NMR (DMSO) δ 2.37 (s, 3H), 3.24 (s, 3H), 6.41 (s,
1H), 7.08 (d, J ) 8.5 Hz, 2H), 7.51 (d, J ) 8.5 Hz, 2H), 7.58 (d,
J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H). HPLC purity (method
1): 98.0%.
3-Ben zyl-2-(4-m eth a n esu lfon ylp h en yl)-6-m eth ylp yr a n -
4-on e (16) was prepared according to method C starting from
79 (7.00 g). Purification by flash chromatography, eluting with
2-(4-Meth a n esu lfon ylp h en yl)-6-m eth yl-3-(4-tr iflu or o-
m eth ylp h en yl)p yr a n -4-on e (7) was prepared according to
method C starting from 70 (1.57 g). Purification by flash
chromatography, eluting with EtOAc/hexane (3:1), gave 0.70
g of the title compound. Recrystallization from ethanol gave
0.43 g (23%) of 7: mp 170 °C; 1H NMR (DMSO) δ 2.40 (s, 3H),
3.24 (s, 3H), 6.45 (s, 1H), 7.37 (d, J ) 8.2 Hz, 2H), 7.59 (d, J
) 8.2 Hz, 2H), 7.69 (d, J ) 8.2 Hz, 2H), 7.90 (d, J ) 8.2 Hz,
2H). HPLC purity (method 1): 99.2%. Anal. (C20H15F3O4S) C,
H, S.
2-(4-Meth an esu lfon ylph en yl)-6-m eth yl-3-(4-m eth ylph en -
yl)p yr a n -4-on e (8) was prepared according to method C
starting from 71 (1.84 g). Purification by flash chromatogra-
phy, eluting with EtOAc, gave 0.32 g (14%) of 8: mp 205 °C;
1H NMR (CDCl3) δ 2.34 (s, 3H), 2.39 (s, 3H), 3.04 (s, 3H), 6.34
(s, 1H), 7.02 (d, J ) 8.0 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 2H), 7.49
(d, J ) 8.2 Hz, 2H), 7.82 (d, J ) 8.2 Hz, 2H). HPLC purity
(method 1): 95.6%.
1
EtOAc/hexane (5:2), gave 1.80 g (21%) of 16: mp 137 °C; H
NMR (CDCl3) δ 2.33 (s, 3H), 3.08 (s, 3H), 3.81 (s, 2H), 6.27 (s,
1H), 7.04-7.06 (m, 2H), 7.13-7.27 (m, 3H), 7.63 (d, J ) 8.0
Hz, 2H), 7.99 (d, J ) 8.0 Hz, 2H). HPLC purity (method 1):
99.4%.
5.2. Syn th esis of P yr on e 17 (Sch em e 2). 1-(4-F lu o-
r op h en yl)-2-(4-m eth ylsu lfa n ylp h en yl)eth a n on e (80). To
a cooled solution of 32.6 g (0.162 mol) of 4-methylsulfanylphe-
nylacetyl chloride and 33.3 g (0.346 mol) of fluorobenzene in
350 mL of carbon disulfide was added 48.5 g (0.364 mol) of
aluminum trichloride in small portions. After being stirred at
room temperature for 24 h, the mixture was poured into HCl/
ice and extracted with CH2Cl2. The combined organic phase
was washed with 2 N NaOH, dried, and evaporated. The
resulting solid was recrystallized from hexane/CHCl3 (95:5)
to give 13.1 g (31%) of the title compound: 1H NMR (CDCl3)
δ 2.47 (s, 3H), 4.21 (s, 2H), 7.10-7.27 (m, 6H), 8.00-8.05 (m,
2H).
1-(4-F lu or op h en yl)-2-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (81) was prepared according to method B starting from
80 (13.1 g). Crystallization from ethyl ether gave 12.8 g (87%)
of 81: 1H NMR (CDCl3) δ 3.07 (s, 3H), 4.39 (s, 2H), 7.18 (dd,
J 1 ) J F-H ) 9.0 Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 7.92 (d, J )
8.5 Hz, 2H), 8.03-8.08 (m, 2H).
3-(3,4-Dich lor op h en yl)-2-(4-m eth a n esu lfon ylp h en yl)-
6-m eth ylp yr a n -4-on e (9) was prepared according to method
C starting from 72 (3.00 g). Purification by flash chromatog-
raphy, eluting with EtOAc/hexane (2:1), gave 2.00 g (60%) of
1
9: mp 160 °C; H NMR (DMSO) δ 2.39 (s, 3H), 3.24 (s, 3H),
6.44 (s, 1H), 7.04 (d, J ) 8.2 Hz, 1H), 7.49 (s, 1H), 7.55 (d, J
) 8.2 Hz, 1H), 7.62 (d, J ) 8.5 Hz, 2H), 7.93 (d, J ) 8.5 Hz,
2H). HPLC purity (method 1): 99.1%. Anal. (C19H14Cl2O4S)
C, H, S.
2-(4-Fluorophenyl)-3-(4-methanesulfonylphenyl)-6-meth-
ylp yr a n -4-on e (17) was prepared according to method C
starting from 81 (1.00 g). Purification by flash chromatogra-
phy, eluting with EtOAc/hexane (1:1), gave 0.40 g (33%) of
3-(2,4-Diflu or op h en yl)-2-(4-m eth a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (10) was prepared according to method
C starting from 73 (5.38 g). Recrystallization from EtOH gave
1.95 g (30%) of 10: mp 208 °C; 1H NMR (CDCl3) δ 2.41 (s,
3H), 3.06 (s, 3H), 6.35 (s, 1H), 6.77 (td, J ) 9.1, 2.4 Hz, 1H),
6.89 (td, J ) 8.3, 1.7 Hz, 1H), 7.17 (dd, J ) 8.3, 6.7 Hz, 1H),
7.52 (d, J ) 8.5 Hz, 2H), 7.88 (d, J ) 8.5 Hz, 2H). HPLC purity
(method 1): 99.0%.
1
17: mp 193 °C; H NMR (DMSO) δ 2.37 (s, 3H), 3.20 (s, 3H),
6.39 (s, 1H), 7.19 (dd, J 1 ) J F-H ) 9.0 Hz, 2H), 7.36-7.39 (m,
2H), 7.36 (d, J ) 8.2 Hz, 2H), 7.83 (d, J ) 8.2 Hz, 2H). HPLC
purity: 97.3%. Anal. (C19H15FO4S) C, H, S.
5.3. Syn t h esis of P yr on es 18 a n d 19 (Sch em e 3).
4-Su lfa m oylben zoic Acid Eth yl Ester (82). To a suspension
of 99.0 g (0.492 mol) of 4-sulfamoylbenzoic acid in 990 mL of
EtOH was added dropwise 990 mL of EtOH saturated with
HCl(g). The mixture was stirred at room temperature over-
night. The insoluble starting material was filtered, and the
solvent was removed under reduced pressure. The resulting
solid was washed with isopropyl ether, filtered, and dried to
give 110.5 g (98%) of the title compound: 1H NMR (DMSO) δ
1.17 (t, J ) 7.5 Hz, 3H), 4.24 (q, J ) 7.5 Hz, 2H), 7.51 (s, 2H),
7.93 (d, J ) 8.5 Hz, 2H), 8.10 (d, J ) 8.5 Hz, 2H).
3-(4-Ch lor o-2-flu or oph en yl)-2-(4-m eth an esu lfon ylph en -
yl)-6-m eth ylp yr a n -4-on e (11) was prepared according to
method C starting from 74 (2.50 g). Purification by flash
chromatography, eluting with EtOAc/hexane (1:1), gave 1.00
1
g (33%) of 11: mp 171 °C; H NMR (DMSO) δ 2.40 (s, 3H),
3.25 (s, 3H), 6.43 (s, 1H), 7.19-7.29 (m, 2H), 7.44 (d, J ) 8.5
Hz, 1H), 7.62 (d, J ) 8.2 Hz, 2H), 7.95 (d, J ) 8.2 Hz, 2H).
HPLC purity (method 1): 95.5%.
2-(4-Meth a n esu lfon ylp h en yl)-6-m eth yl-3-(n a p h th a len -
2-yl)p yr a n -4-on e (12) was prepared according to method C
starting from 75 (14.5 g). Purification by flash chromatogra-
phy, eluting with EtOAc/hexane (3:1), gave 1.10 g (6%) of 12:
mp 122-123 °C; 1H NMR (CDCl3) δ 2.42 (s, 3H), 2.99 (s, 3H),
4-(Diben zylsu lfa m oyl)ben zoic Acid Eth yl Ester (83).
To a suspension of 110.5 g (0.48 mol) of 82 and 199 g (1.44
mol) of K2CO3 in 400 mL of acetone was added dropwise a

3882 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
solution of 164 g (0.96 mol) of benzyl chloride in 100 mL of
acetone. The mixture was refluxed for 5 h. After the mixture
was cooled, the solvent was evaporated, the resulting solid was
suspended in water, and the sample was extracted with CH2-
Cl2. The combined organic layer was washed with water dried,
and the solvent was removed under reduced pressure. The
resulting solid was washed with hexane, filtered, and dried
to give 176.4 g (89%) of 83: 1H NMR (CDCl3) δ 1.42 (t, J ) 7.5
Hz, 3H), 4.35 (s, 4H), 4.43 (q, J ) 7.5 Hz, 2H), 7.04-7.06 (m,
4H), 7.20-7.24 (m, 6H), 7.88 (d, J ) 8.5 Hz, 2H), 8.13 (d, J )
8.5 Hz, 2H).
4-(Diben zylsu lfa m oyl)ben zoic Acid (84). A suspension
of 176.4 g (0.43 mol) of 83 and 315 mL of 2 N NaOH in 900
mL of EtOH was refluxed for 1 h. The mixture was cooled,
and the solvent was removed under reduced pressure. The
residue was suspended in water and the mixture was acidified
with HCl(conc). The resulting solid was filtered, washed with
water, and dried to yield 162.3 g (99%) of 84: 1H NMR (DMSO)
δ 4.29 (s, 4H), 7.06-7.09 (m, 4H), 7.17-7.24 (m, 6H), 7.78 (d,
J ) 8.5 Hz, 2H), 8.09 (d, J ) 8.5 Hz, 2H).
4-D i b e n z y ls u lfa m o y l-N -m e t h o x y -N -m e t h y lb e n z -
a m id e (85). A solution of 24 g (63 mmol) of 84 in 50 mL of
thionyl chloride was refluxed for 2.5 h, and the excess thionyl
chloride was removed under reduced pressure. The resulting
oil was dissolved in 150 mL of CH2Cl2 and added slowly to a
solution of 7.37 g (75.6 mmol) of N,O-dimethylhydroxylamine
hydrochloride and 21.8 mL (151 mmol) of triethylamine in 150
mL of CH2Cl2. The mixture was stirred at room temperature
for 16 h. The insoluble material was filtered off, and the solvent
was removed under reduced pressure. The residual oil was
purified by flash chromatography, eluting with EtOAc/hexane
(1:1), to give 22 g (85%) of the title compound: 1H NMR
(CDCl3) δ 3.40 (s, 3H), 3.57 (s, 3H), 4.37 (s, 4H), 7.05-7.07
(m, 4H), 7.20-7.29 (m, 6H), 7.80 (d, J ) 8.5 Hz, 2H), 7.88 (d,
J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of In ter m ed ia tes
86 a n d 87. Meth od D. N,N-Diben zyl-4-p h en yla cetylben -
zen esu lfon a m id e (86). To a suspension of 2 g (82.4 mmol)
of magnesium in 20 mL of anhydrous THF was slowly added
a solution of 10.4 g (82.4 mmol) of benzyl chloride in 100 mL
of anhydrous THF. When the reaction was completed, a
solution of 7.00 g (16.5 mmol) of 85 in 50 mL of anhydrous
THF was slowly added while the temperature was maintained
at 0 °C. After being stirred at the same temperature for half
an hour, the reaction mixture was poured into a saturated
ammonium chloride solution and extracted with ethyl ether
and the organic extracts were dried. The solvent was removed
under reduced pressure and the residual oil was purified by
flash chromatography, eluting with hexane/EtOAc (1:3), to give
6.80 g (90%) of 86: 1H NMR (CDCl3) δ 4.31 (s, 2H), 4.34 (s,
4H), 7.00-7.06 (m, 4H), 7.17-7.20 (m, 6H), 7.25-7.37 (m, 5H),
7.91 (d, J ) 8.5 Hz, 2H), 8.07 (d, J ) 8.5 Hz, 2H).
N ,N -Dib e n zyl-4-[2-(4-flu or op h e n yl)a ce t yl]b e n ze n e -
su lfon a m id e (87) was prepared according to method D
starting from 85 (10.75 g) and 4-fluorobenzyl chloride. Crystal-
lization from ethyl ether/pentane (1:2) gave 5.60 g (47%) of
87: 1H NMR (CDCl3) δ 4.34 (s, 4H), 4.51 (s, 2H), 7.07-7.12
(m, 4H), 7.18-7.23 (m, 8H), 7.31-7.36 (m, 2H), 8.04 (d, J )
8.5 Hz, 2H), 8.22 (d, J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of P yr on es 18
a n d 19. Meth od E. 4-(6-Meth yl-4-oxo-3-p h en yl-4H-p yr a n -
2-yl)ben zen esu lfon a m id e (18). A solution of 94.0 g of
polyphosphoric acid in 120 mL of acetic acid was heated at
140 °C. Then a suspension of 9.40 g (20.7 mmol) of 86 in 20
mL of acetic acid was added. The mixture was heated at 140
°C for 16 h. After cooling, the reaction mixture was poured
into ice/water and extracted with EtOAc. The organic layer
was dried, and the solvent was removed under reduced
pressure. To the residual oil was added 38 mL of concentrated
sulfuric acid, and the mixture was stirred at 0 °C for 10 min,
was stirred an additional 60 min at room temperature, and
was poured into ice/water. The precipitated solid was collected
by filtration. Purification by flash chromatography, eluting
with EtOAc/hexane (1:1), gave 1.53 g (22%) of 18: mp 218 °C;
1H NMR (DMSO) δ 2.37 (s, 3H), 6.38 (s, 1H), 7.09-7.12 (m,
2H), 7.28-7.30 (m, 3H), 7.44 (s, 2H), 7.47 (d, J ) 8.5 Hz, 2H),
7.71 (d, J ) 8.5 Hz, 2H). HPLC purity: 98.6%. Anal. (C18H15-
NO4S) C, H, N, S.
4-[3-(4-F lu or op h en yl)-6-m et h yl-4-oxo-4H-p yr a n -2-yl]-
ben zen esu lfon a m id e (19) was prepared according to method
F starting from 87 (5.50 g). Purification by flash chromatog-
raphy, eluting with CH2Cl2/EtOAc/AcOH (78:10:1), gave 1.01
1
g (26%) of 19: mp 247 °C; H NMR (DMSO) δ 2.37 (s, 3H),
6.39 (s, 1H), 7.15 (d, J ) 7.5 Hz, 4H), 7.46 (s, 2H), 7.49 (d, J
) 8.5 Hz, 2H), 7.75 (d, J ) 8.5 Hz, 2H). HPLC purity: 98.2%.
Anal. (C18H14NFO4S) C, H, N, S.
5.4. Syn th esis of P yr on es 20-40 (Sch em e 4). Gen er a l
P r oced u r e for th e Syn th esis of In ter m ed ia tes 88-108.
Meth od F. 2-(4-Flu or oph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (88). To a solution of 0.7 g (6.1 mmol) of
4-fluorophenol in 5 mL of CH2Cl2 and 1.28 g (9.2 mmol) of K2-
CO3 in 4 mL of water was added 0.1 g (0.3 mmol) of
tetrabutylammonium hydrogen sulfate and a solution of 1.5 g
(6.1 mmol) of 2-bromo-1-(4-methylsulfanylphenyl)ethanone16
in 5 mL of CH2Cl2. The mixture was stirred at room temper-
ature for 16 h. Water was added, the organic phase was
decanted, and the basic phase was extracted with CH2Cl2. The
organic solution was dried, and the solvent was removed under
reduced pressure. The resulting solid was washed with ethyl
ether to yield 1.1 g (65%) of the title compound: 1H NMR
(CDCl3) δ 2.52 (s, 3H), 5.17 (s, 2H), 6.85-7.00 (m, 4H), 7.27
(d, J ) 8.5 Hz, 2H), 7.89 (d, J ) 8.5 Hz, 2H).
2-(4-Ch lor op h en oxy)-1-(4-m eth ylsu lfa n ylp h en yl)eth a -
n on e (89) was prepared according to method F starting from
4-chlorophenol (21 g). Crystallization from ethyl ether gave
42.7 g (90%) of 89: 1H NMR (CDCl3) δ 2.55 (s, 3H), 5.20 (s,
2H), 6.88 (d, J ) 8.5 Hz, 2H), 7.25 (d, J ) 8.5 Hz, 2H), 7.30 (d,
J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(2-Br om op h en oxy)-1-(4-m eth ylsu lfa n ylp h en yl)eth a -
n on e (90) was prepared according to method F starting from
2-bromophenol (4.9 g). Crystallization from ethyl ether gave
7.45 g (77%) of 90: 1H NMR (CDCl3) δ 2.53 (s, 3H), 5.30 (s,
2H), 6.87 (m, 2H), 7.20 (d, J ) 8.5 Hz, 1H), 7.33 (d, J ) 8.5
Hz, 2H), 7.57 (d, J ) 8.5 Hz, 1H), 7.97 (d, J ) 8.5 Hz, 2H).
2-(3-Br om op h en oxy)-1-(4-m eth ylsu lfa n ylp h en yl)eth a -
n on e (91) was prepared according to method F starting from
3-bromophenol (5.3 g). Crystallization from ethyl ether gave
6.7 g (65%) of 91: 1H NMR (CDCl3) δ 2.55 (s, 3H), 5.23 (s,
2H), 6.88 (m, 1H), 7.15 (m, 3H), 7.33 (d, J ) 8.5 Hz, 2H), 7.93
(d, J ) 8.5 Hz, 2H).
2-(4-Br om op h en oxy)-1-(4-m eth ylsu lfa n ylp h en yl)eth a -
n on e (92) was prepared according to method F starting from
4-bromophenol (4.87 g). Crystallization from ethyl ether gave
7.86 g (83%) of 92: 1H NMR (CDCl3) δ 2.54 (s, 3H), 5.20 (s,
2H), 6.80 (d, J ) 8.5 Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.40 (d,
J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Iod op h en oxy)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (93) was prepared according to method F starting from
4-iodophenol (1.8 g). Crystallization from ethyl ether and
EtOAc gave 2.5 g (81%) of 93: 1H NMR (CDCl3) δ 2.53 (s, 3H),
5.20 (s, 2H), 6.73 (d, J ) 8.5 Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H),
7.60 (d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Tr iflu or om e t h ylp h e n oxy)-1-(4-m e t h ylsu lfa n yl-
p h en yl)eth a n on e (94) was prepared according to method F
starting from 4-trifluoromethylphenol (1.3 g). Crystallization
from ethyl ether gave 2.6 g (99%) of 94: 1H NMR (CDCl3) δ
2.53 (s, 3H), 5.33 (s, 2H), 7.00 (d, J ) 8.5 Hz, 2H), 7.30 (d, J
) 8.5 Hz, 2H), 7.57 (d, J ) 8.5 Hz, 2H), 7.93 (d, J ) 8.5 Hz,
2H).
2-(4-P entafluoroethylphenoxy)-1-(4-methylsulfanylphen-
yl)eth a n on e (95) was prepared according to method F start-
ing from 4-pentafluoroethylphenol (0.84 g) and 2-bromo-1-(4-
methylsulfanylphenyl)ethanone. Crystallization from ethyl
ether gave 1.5 g (100%) of 95: MS (M+), m/z: 376.
2-(4-T r iflu or o m e t h ox yp h e n oxy )-1-(4-m e t h y lsu lfa -
n ylp h en yl)eth a n on e (96) was prepared according to method
F starting from 4-trifluoromethoxyphenol (1.4 g). Crystalliza-
tion from ethyl ether gave 2.37 g (86%) of 96: 1H NMR (CDCl3)
δ 2.53 (s, 3H), 5.20 (s, 2H), 6.93 (d, J ) 8.5 Hz, 2H), 7.17 (d, J
) 8.5 Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz,
2H).

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3883
2-(4-Nit r op h en oxy)-1-(4-m et h ylsu lfa n ylp h en yl)et h a -
n on e (97) was prepared according to method F starting from
4-nitrophenol (2.1 g). Crystallization from ethyl ether gave 4.6
g (100%) of 97: 1H NMR (DMSO) δ 2.60 (s, 3H), 5.80 (s, 2H),
7.20 (d, J ) 8.5 Hz, 2H), 7.43 (d, J ) 8.5 Hz, 2H), 7.97 (d, J )
8.5 Hz, 2H), 8.20 (d, J ) 8.5 Hz, 2H).
4-[2-(4-Meth ylsu lfan ylph en yl)-2-oxoeth oxy]ben zoic acid
m eth yl ester (98) was prepared according to method F
starting from 4-hydroxybenzoic acid methyl ester (2.2 g).
Crystallization from ethyl ether/EtOAc gave 2.7 g (59%) of
98: 1H NMR (CDCl3) δ 2.53 (s, 3H), 3.90 (s, 3H), 5.30 (s, 2H),
6.97 (d, J ) 8.5 Hz, 2H), 7.30 (d, J ) 8.5 Hz, 2H), 7.90 (d, J )
8.5 Hz, 2H), 8.00 (d, J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of In ter m ed ia tes
109-112. Meth od B. 2-(4-F lu or op h en oxy)-1-(4-m eth a n e-
su lfon ylp h en yl)eth a n on e (109) was prepared according to
method B starting from 88 (1.10 g). Crystallization from ethyl
ether gave 0.75 g (60%) of 109: 1H NMR (DMSO) δ 3.32 (s,
3H), 5.62 (s, 2H), 7.01-7.04 (m, 2H), 7.05-7.17 (m, 2H), 8.13
(d, J ) 8.0 Hz, 2H), 8.25 (d, J ) 8.0 Hz, 2H).
2-(4-Br om op h e n oxy)-1-(4-m e t h a n e su lfon ylp h e n yl)-
eth a n on e (110) was prepared according to method B starting
from 92 (7.86 g). Crystallization from ethyl ether gave 7.55 g
(88%) of 110: 1H NMR (CDCl3) δ 3.33 (s, 3H), 5.66 (s, 2H),
7.00 (d, J ) 9.0 Hz, 2H), 7.46 (d, J ) 9.0 Hz, 2H), 8.12 (d, J )
9.0 Hz, 2H), 8.24 (d, J ) 9.0 Hz, 2H).
2-(2,4-Diflu or op h en oxy)-1-(4-m et h ylsu lfa n ylp h en yl)-
eth a n on e (99) was prepared according to method F starting
from 2,4-difluorophenol (18.6 g). Crystallization from ethyl
ether gave 38.6 g (92%) of 99: 1H NMR (CDCl3) δ 2.55 (s, 3H),
5.28 (s, 2H), 6.73-7.00 (m, 3H), 7.28 (d, J ) 8.5 Hz, 2H), 7.90
(d, J ) 8.5 Hz, 2H).
2-(3,4-Diflu or op h en oxy)-1-(4-m et h ylsu lfa n ylp h en yl)-
eth a n on e (100) was prepared according to method F starting
from 3,4-difluorophenol (3.5 g). Crystallization from ethyl ether
gave 3.3 g (44%) of 100: 1H NMR (CDCl3) δ 2.55 (s, 3H), 5.20
(s, 2H), 6.63 (m, 1H), 6.78 (m, 1H), 7.05 (m, 1H), 7.30 (d, J )
8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(2,4-Diflu or op h en oxy)-1-(4-m eth a n esu lfon ylp h en yl)-
eth a n on e (111) was prepared according to method B starting
from 99 (6.60 g). Crystallization from ethyl ether gave 4.97 g
(65%) of 111: 1H NMR (DMSO) δ 3.31 (s, 3H), 5.72 (s, 2H),
6.93-7.05 (m, 1H), 7.15-7.36 (m, 2H), 8.12 (d, J ) 8.5 Hz,
2H), 8.22 (d, J ) 8.5 Hz, 2H).
2-(3,4-Diflu or op h en oxy)-1-(4-m eth a n esu lfon ylp h en yl)-
eth a n on e (112) was prepared according to method B starting
from 100 (3.30 g). Crystallization from ethyl ether gave 2.67
g (73%) of 112: 1H NMR (CDCl3) δ 3.11 (s, 3H), 5.26 (s, 2H),
6.64-6.68 (m, 1H), 6.76-6.81 (m, 1H), 7.03-7.14 (m, 1H), 8.10
(d, J ) 8.0 Hz, 2H), 8.16 (d, J ) 8.0 Hz, 2H).
2-(3,4-Dich lor op h en oxy)-1-(4-m eth ylsu lfa n ylp h en yl)-
eth a n on e (101) was prepared according to method F starting
from 3,4-dichlorophenol (4.57 g). Crystallization from ethyl
ether gave 9.2 g (100%) of 101: 1H NMR (CDCl3) δ 2.53 (s,
3H), 5.20 (s, 2H), 6.80 (d, J ) 8.5 Hz, 1H), 7.03 (s, 1H), 7.30
(m, 3H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Ch lor o-2-flu or oph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (102) was prepared according to method F
starting from 4-chloro-2-fluorophenol (0.47 g). Crystallization
from pentane/ethyl ether (4:1) gave 0.63 g (62%) of 102: 1H
NMR (CDCl3) δ 2.53 (s, 3H), 5.30 (s, 2H), 6.83-7.17 (m, 3H),
7.30 (d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Br om o-2-flu or oph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (103) was prepared according to method F
starting from 4-bromo-2-fluorophenol (5.1 g). Crystallization
from ethyl ether gave 6.8 g (78%) of 103: 1H NMR (CDCl3) δ
2.55 (s, 3H), 5.30 (s, 2H), 6.83 (dd, J HH ) J HF ) 5.0, 1H), 7.15
(m, 1H), 7.25-7.33 (m, 3H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(4-Br om o-2-ch lor oph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (104) was prepared according to method F
starting from 4-bromo-2-chlorophenol (1.7 g). Crystallization
from ethyl ether gave 2.6 g (87%) of 104: 1H NMR (CDCl3) δ
2.53 (s, 3H), 5.27 (s, 2H), 6.73 (d, J ) 8.5 Hz, 2H), 7.27 (m,
3H), 7.53 (s, 1H), 7.93 (d, J ) 8.5 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of In ter m ed ia tes
113-129. Meth od G. 2-(4-Ch lor op h en oxy)-1-(4-m eth a n e-
su lfon ylp h en yl)eth a n on e (113). To a cooled solution of 42.7
g (0.146 mol) of 89 in 600 mL of acetone was added a solution
of 164.4 g (0.267 mol) of Oxone in 600 mL of water. The
mixture was stirred at room temperature overnight and
diluted with 600 mL of water. The resulting solid was filtered
off, washed with water, and dried to yield 39.0 g (82%) of the
title compound: 1H NMR (DMSO) δ 3.30 (s, 3H), 5.65 (s, 2H),
7.03 (d, J ) 8.5 Hz, 2H), 7.32 (d, J ) 8.5 Hz, 2H), 8.12 (d, J )
8.5 Hz, 2H), 8.24 (d, J ) 8.5 Hz, 2H).
2-(2-Br om op h e n oxy)-1-(4-m e t h a n e su lfon ylp h e n yl)-
eth a n on e (114) was prepared according to method G starting
from 90 (7.40 g). Crystallization from water gave 7.60 g (94%)
of 114: 1H NMR (CDCl3) δ 3.07 (s, 3H), 5.30 (s, 2H), 6.80-
6.94 (m, 2H), 7.20-7.26 (m, 1H), 7.53 (d, J ) 7.5 Hz, 1H), 8.08
(d, J ) 9.0 Hz, 2H), 8.23 (d, J ) 9.0 Hz, 2H).
2-(3-Br om op h e n oxy)-1-(4-m e t h a n e su lfon ylp h e n yl)-
eth a n on e (115) was prepared according to method G starting
from 91 (6.69 g). Crystallization from water gave 6.48 g (88%)
of 115: 1H NMR (DMSO) δ 3.33 (s, 3H), 5.72 (s, 2H), 7.03-
7.06 (m, 1H), 7.17 (d, J ) 8.0 Hz, 1H), 7.25 (d, J ) 8.0 Hz,
1H), 7.32 (s, 1H), 8.13 (d, J ) 8.0 Hz, 2H), 8.24 (d, J ) 8.0 Hz,
2H).
2-(4-Iod op h en oxy)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (116) was prepared according to method G starting from
93 (2.50 g). Crystallization from water gave 2.80 g (100%) of
116: 1H NMR (CDCl3) δ 3.09 (s, 3H), 5.24 (s, 2H), 6.71 (d, J )
9.0 Hz, 1H), 7.60 (d, J ) 9.0 Hz, 1H), 8.09 (d, J ) 8.0 Hz, 2H),
8.18 (d, J ) 8.0 Hz, 2H).
2-(4-Tr iflu or om e t h ylp h e n oxy)-1-(4-m e t h a n e su lfo-
n ylph en yl)eth an on e (117) was prepared according to method
G starting from 94 (2.88 g). Crystallization from ethyl ether
gave 1.52 g (48%) of 117: 1H NMR (CDCl3) δ 3.10 (s, 3H), 5.34
(s, 2H), 7.00 (d, J ) 8.5 Hz, 2H), 7.56 (d, J ) 8.5 Hz, 2H), 8.10
(d, J ) 8.5 Hz, 2H), 8.17 (d, J ) 8.5 Hz, 2H).
2-(4-P e n t a flu or oe t h ylp h e n oxy)-1-(4-m e t h a n e su lfo-
n ylph en yl)eth an on e (118) was prepared according to method
G starting from 95 (1.69 g). Purification by flash chromatog-
raphy, eluting with EtOAc/hexane (2:3), gave 0.23 g (14%) of
118: 1H NMR (CDCl3) δ 3.09 (s, 3H), 5.33 (s, 2H), 7.03 (d, J )
9.0 Hz, 2H), 7.55 (d, J ) 9.0 Hz, 2H), 8.11 (d, J ) 8.0 Hz, 2H),
8.20 (d, J ) 8.0 Hz, 2H).
2-(4-Tr iflu or om et h oxyp h en oxy)-1-(4-m et h a n esu lfo-
n ylph en yl)eth an on e (119) was prepared according to method
G starting from 96 (2.37 g). Crystallization from water gave
2.74 g (100%) of 119: 1H NMR (CDCl3) δ 3.11 (s, 3H), 5.26 (s,
2H), 6.92 (d, J ) 8.0 Hz, 2H), 7.19 (d, J ) 8.0 Hz, 2H), 8.11 (d,
J ) 8.0 Hz, 2H), 8.20 (d, J ) 8.0 Hz, 2H).
2-(4-Flu or o-2-m eth ylph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (105) was prepared according to method F
starting from 4-fluoro-2-methylphenol (5.8 g). Crystallization
from ethyl ether gave 12.1 g (91%) of 105: 1H NMR (CDCl3) δ
2.28 (s, 3H), 2.55 (s, 3H), 5.20 (s, 2H), 6.65-6.90 (m, 3H), 7.30
(d, J ) 8.5 Hz, 2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(2-Ch lor o-4-m eth ylph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (106) was prepared according to method F
starting from 2-chloro-4-methylphenol (5.4 g). Crystallization
from ethyl ether gave 10.4 g (96%) of 106: 1H NMR (CDCl3) δ
2.25 (s, 3H), 2.55 (s, 3H), 5.25 (s, 2H), 6.78 (d, J ) 8.7 Hz,
1H), 6.95 (d, J ) 8.7 Hz, 1H), 7.20 (s, 1H), 7.30 (d, J ) 8.5 Hz,
2H), 7.95 (d, J ) 8.5 Hz, 2H).
2-(4-Ch lor o-2-m eth ylph en oxy)-1-(4-m eth ylsu lfan ylph en -
yl)eth a n on e (107) was prepared according to method F
starting from 4-chloro-2-methylphenol (3.5 g). Crystallization
from ethyl ether gave 6.35 g (84%) of 107: 1H NMR (CDCl3) δ
2.25 (s, 3H), 2.55 (s, 3H), 5.20 (s, 2H), 6.65 (d, J ) 8.7 Hz,
1H), 7.05 (d, J ) 8.7 Hz, 1H), 7.15 (s, 1H), 7.30 (d, J ) 8.5 Hz,
2H), 7.90 (d, J ) 8.5 Hz, 2H).
2-(2-C h lor o-4-m e t h o xy p h e n o xy)-1-(4-m e t h y lsu lfa -
n ylph en yl)eth an on e (108) was prepared according to method
F starting from 2-chloro-4-methoxyphenol (1.3 g). Crystalliza-
tion from hexane/ethyl ether gave 1.88 g (73%) of 108: 1H
NMR (CDCl3) δ 2.53 (s, 3H), 3.73 (s, 3H), 5.20 (s, 2H), 6.73-
6.97 (m, 3H), 7.30 (d, J ) 8.5 Hz, 2H), 7.97 (d, J ) 8.5 Hz,
2H).
2-(4-Nitr op h en oxy)-1-(4-m eth a n esu lfon ylp h en yl)eth a -
n on e (120) was prepared according to method G starting from

3884 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
97 (4.60 g). Crystallization from water gave 3.70 g (74%) of
120: 1H NMR (DMSO) δ 3.35 (s, 3H), 5.89 (s, 2H), 7.26 (d, J
) 9.0 Hz, 2H), 8.11-8.27 (m, 6H).
poured into ice/water and extracted with EtOAc. The organic
layer was washed with saturated sodium bicarbonate, water,
and brine, dried, and evaporated to give a residue that was
purified by flash chromatography, eluting with hexane/EtOAc
(1:3), to give 2.28 g (21%) of the title compound: mp 197 °C;
1H NMR (DMSO) δ 2.43 (s, 3H), 3.26 (s, 3H), 6.47 (s, 1H), 6.98-
7.04 (m, 2H), 7.09-7.15 (m, 2H), 8.07 (s, 4H). HPLC purity
(method 1): 99.3%. Anal. (C19H15FO5S) H, S. C: calcd, 60.37;
found, 60.96.
4-[2-(4-Met h a n esu lfon ylp h en yl)-2-oxoet h oxy]b en zo-
ic a cid m eth yl ester (121) was prepared according to method
G starting from 98 (2.67 g). Crystallization from water gave
2.38 g (81%) of 121: 1H NMR (CDCl3) δ 3.08 (s, 3H), 3.90 (s,
3H), 5.35 (s, 2H), 6.98 (d, J ) 8.0 Hz, 2H), 8.02 (d, J ) 8.0 Hz,
2H), 8.11 (d, J ) 8.0 Hz, 2H), 8.20 (d, J ) 8.0 Hz, 2H).
2-(3,4-Dich lor op h en oxy)-1-(4-m eth a n esu lfon ylp h en yl)-
eth a n on e (122) was prepared according to method G starting
from 100 (8.00 g). Crystallization from ethyl ether gave 7.28
g (83%) of 122: 1H NMR (CDCl3) δ 3.09 (s, 3H), 5.24 (s, 2H),
6.82 (d, J ) 9.0 Hz, 1H), 7.01 (s, 1H), 7.34 (d, J ) 9.0 Hz, 1H),
8.07 (d, J ) 9.0 Hz, 2H), 8.13 (d, J ) 9.0 Hz, 2H).
2-(4-Chloro-2-fluorophenoxy)-1-(4-methanesulfonylphen-
yl)eth a n on e (123) was prepared according to method G
starting from 102 (0.63 g). Crystallization from water gave 0.58
g (84%) of 123: 1H NMR (CDCl3) δ 3.11 (s, 3H), 5.33 (s, 2H),
6.92 (t, J F-H ) 13.0 Hz, 1H), 7.00-7.20 (m, 2H), 8.11 (d, J )
8.0 Hz, 2H), 8.18 (d, J ) 8.0 Hz, 2H).
2-(4-Bromo-2-fluorophenoxy)-1-(4-methanesulfonylphen-
yl)eth a n on e (124) was prepared according to method G
starting from 103 (6.80 g). Crystallization from water gave 7.60
g (100%) of 124: 1H NMR (DMSO) δ 3.32 (s, 3H), 5.80 (s, 2H),
7.10 (t, J ) 7.5 Hz, 1H), 7.37 (t, J ) 7.5 Hz, 1H), 7.60 (d, J )
7.5 Hz, 1H), 8.13 (d, J ) 9.0 Hz, 2H), 8.24 (d, J ) 9.0 Hz, 2H).
2-(4-Bromo-2-chlorophenoxy)-1-(4-methanesulfonylphen-
yl)eth a n on e (125) was prepared according to method G
starting from 104 (2.59 g). Crystallization from water gave 2.18
g (78%) of 125: 1H NMR (CDCl3) δ 3.13 (s, 3H), 5.32 (s, 2H),
6.77 (d, J ) 9.0 Hz, 1H), 7.32 (d, J ) 9.0 Hz, 1H), 7.56 (s, 1H),
8.12 (d, J ) 7.5 Hz, 2H), 8.24 (d, J ) 7.5 Hz, 2H).
3-(4-Ch lor op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (21) was prepared according to method
H starting from 113 (2.7 g). Purification by flash chromatog-
raphy with silica gel and hexane/EtOAc (2:3) as eluent gave
1
0.42 g (13%) of 21 as an off-white solid: mp 204 °C; H NMR
(DMSO) δ 2.44 (s, 3H), 3.26 (s, 3H), 6.48 (s, 1H), 7.20 (d, J )
9.0 Hz, 2H), 7.34 (d, J ) 9.0 Hz, 2H), 8.06 (s, 4H). HPLC purity
(method 1): 99.1%. Anal. (C19H15ClO5S) C, H, S.
3-(2-Br om op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (22) was prepared according to method
I starting from 114 (2.25 g). Purification by flash chromatog-
raphy, eluting with EtOAc, gave 0.87 g (33%) of 22: mp 197-
1
199 °C; H NMR (CDCl3) δ 2.46 (s, 3H), 3.11 (s, 3H), 6.43 (s,
1H), 6.67 (d, J ) 7.5 Hz, 1H), 6.92 (t, J ) 7.5 Hz, 1H), 7.18 (t,
J ) 7.5 Hz, 1H), 7.62 (t, J ) 7.5 Hz, 1H), 8.04 (d, J ) 9.0 Hz,
2H), 8.18 (d, J ) 9.0 Hz, 2H). HPLC purity (method 1): 98.7%.
3-(3-Br om op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (23) was prepared according to method
I starting from 115 (7.24 g). Purification by flash chromatog-
raphy, eluting with hexane/EtOAc (1:3), gave 1.12 g (15%) of
23: 1H NMR (CDCl3) δ 2.45 (s, 3H), 3.09 (s, 3H), 6.40 (s, 1H),
6.91-6.93 (m, 1H), 7.08 (s, 1H), 7.15-7.20 (m, 2H), 8.03 (d, J
) 8.5 Hz, 2H), 8.07 (d, J ) 8.5 Hz, 2H). HPLC purity (method
1): 96.3%.
3-(4-Br om op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (24) was prepared according to method
I starting from 110 (5.3 g). Purification by flash chromatog-
raphy, eluting with hexane/EtOAc (2:5), gave 1.7 g (27%) of
2-(4-F lu or o-2-m e t h y lp h e n ox y )-1-(4-m e t h a n e su lfo-
n ylph en yl)eth an on e (126) was prepared according to method
G starting from 105 (12.1 g). Crystallization from water gave
11.2 g (83%) of 126: 1H NMR (DMSO) δ 2.22 (s, 3H), 3.30 (s,
3H), 5.63 (s, 2H), 6.89-7.06 (m, 3H), 8.08 (d, J ) 8.0 Hz, 2H),
8.21 (d, J ) 8.0 Hz, 2H).
2-(2-Ch lor o-4-m e t h ylp h e n oxy)-1-(4-m e t h a n e su lfo-
n ylph en yl)eth an on e (127) was prepared according to method
G starting from 106 (10.4 g). Crystallization from water gave
10.0 g (88%) of 127: 1H NMR (DMSO) δ 2.23 (s, 1H), 3.32 (s,
3H), 5.74 (s, 2H), 7.02-7.04 (m, 2H), 7.24 (s, 1H), 8.12 (d, J )
8.0 Hz, 2H), 8.22 (d, J ) 8.0 Hz, 2H).
2-(4-Ch lor o-2-m e t h ylp h e n oxy)-1-(4-m e t h a n e su lfo-
n ylph en yl)eth an on e (128) was prepared according to method
G starting from 107 (6.27 g). Crystallization from water gave
6.40 g (92%) of 128: 1H NMR (DMSO) δ 2.23 (s, 3H), 3.31 (s,
3H), 5.68 (s, 2H), 6.96 (d, J ) 8.5 Hz, 1H), 7.15 (d, J ) 8.5 Hz,
1H), 7.25 (s, 1H), 8.12 (d, J ) 8.5 Hz, 2H), 8.24 (d, J ) 8.5 Hz,
2H).
2-(2-Ch lor o-4-m et h oxyp h en oxy)-1-(4-m et h a n esu lfo-
n ylph en yl)eth an on e (129) was prepared according to method
G starting from 108 (1.88 g). Crystallization from water gave
2.00 g (97%) of 129: 1H NMR (CDCl3) δ 3.08 (s, 3H), 3.78 (s,
3H), 5.24 (s, 2H), 6.71-7.00 (m, 3H), 8.08 (d, J ) 8.0 Hz, 2H),
8.23 (d, J ) 8.0 Hz, 2H).
Gen er a l P r oced u r e for th e Syn th esis of P yr on es 20-
40. 3-(4-F lu or op h en oxy)-2-(4-m eth a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (20). Meth od H. A solution of 7.50 g of
polyphosphoric acid in 9 mL of acetic acid was heated at 120
°C. Then a suspension of 0.75 g (2.4 mmol) of 109 in 2 mL of
acetic acid was added. The mixture was heated at 120 °C for
4 h. After cooling, the reaction mixture was poured into ice/
water and extracted with EtOAc. The organic solution was
dried, and the solvent was removed under reduced pressure.
The residual oil was purified by flash chromatography, eluting
with EtOAc/hexane (1:1), to give 0.26 g (11%) of the title
compound.
Meth od I. A solution of 82 g of polyphosphoric acid in 11.5
mL of acetic anhydride was heated to 100 °C during 10 min
with mechanical stirring. Then the mixture was allowed to
cool to 30 °C and 8.97 g of compound 109 were added in
portions. Then the reaction mixture was heated to 100 °C for
4 h with stirring. After cooling, the reaction mixture was
1
24: mp 188 °C; H NMR (CDCl3) δ 2.44 (s, 3H), 3.06 (s, 3H),
6.36 (s, 1H) 6.89 (d, J ) 9.0 Hz, 2H), 7.20 (d, J ) 9.0 Hz, 2H),
8.00 (d, J ) 9.0 Hz, 2H), 8.07 (d, J ) 9.0 Hz, 2H). HPLC purity
(method 1): 99.4%.
3-(4-Iodoph en oxy)-2-(4-m eth an esu lfon ylph en yl)-6-m eth -
ylp yr a n -4-on e (25) was prepared according to method I
starting from 116 (2.8 g). Purification by flash chromatogra-
phy, eluting with hexane/EtOAc (1:2), gave 0.43 g (14%) of
1
25: mp 223-226 °C; H NMR (CDCl3) δ 2.46 (s, 3H), 3.07 (s,
3H), 6.36 (s, 1H), 6.73 (d, J ) 8.9 Hz, 2H), 7.57 (d, J ) 8.9 Hz,
2H), 8.00 (d, J ) 8.7 Hz, 2H), 8.06 (d, J ) 8.7 Hz, 2H). HPLC
purity (method 1): 97.3%.
3-(4-Tr iflu or om e t h ylp h e n oxy)-2-(4-m e t h a n e su lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (26) was prepared accord-
ing to method I starting from 117 (1.53 g). Purification by flash
chromatography, eluting with EtOAc, gave 0.39 g (22%) of
1
26: mp 206-208 °C; H NMR (CDCl3) δ 2.47 (s, 3H), 3.07 (s,
3H), 6.38 (s, 1H), 7.03 (d, J ) 8.4 Hz, 2H), 7.55 (d, J ) 8.4 Hz,
2H), 8.01 (d, J ) 8.7 Hz, 2H), 8.06 (d, J ) 8.7 Hz, 2H). HPLC
purity (method 1): 98.9%.
3-(4-P e n t a flu or oe t h ylp h e n oxy)-2-(4-m e t h a n e su lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (27) was prepared accord-
ing to method I starting from 118 (0.35 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2:5), gave 0.05
g (12%) of 27: mp 162-163 °C; 1H NMR (CDCl3) δ 2.48 (s,
3H), 3.07 (s, 3H), 6.39 (s, 1H), 7.04 (d, J ) 8.4 Hz, 2H), 7.52
(d, J ) 8.4 Hz, 2H), 8.04 (m, 4H). HPLC purity (method 1):
95.0%.
3-(4-Tr iflu or om et h oxyp h en oxy)-2-(4-m et h a n esu lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (28) was prepared accord-
ing to method I starting from 119 (2.74 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2:5), gave 0.24
g (8%) of 28: mp 156-157 °C; 1H NMR (CDCl3) δ 2.47 (s, 3H),
3.08 (s, 3H), 6.37 (s, 1H), 6.95 (d, J ) 9.3 Hz, 2H), 7.20 (d, J
) 9.3 Hz, 2H), 8.02 (d, J ) 9.2 Hz, 2H), 8.08 (d, J ) 9.2 Hz,
2H). HPLC purity (method 1): 96.2%.
3-(4-Nit r op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (29) was prepared according to method
I starting from 120 (3.70 g). Purification by flash chromatog-

2-Phenylpyran-4-ones
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15 3885
raphy, eluting with hexane/EtOAc (3:7), gave 1.46 g (33%) of
29: mp 252°C; H NMR (DMSO) δ 2.46 (s, 3H), 3.26 (s, 3H),
3-(4-Ch lor o-2-m e t h ylp h e n oxy)-2-(4-m e t h a n e su lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (39) was prepared accord-
ing to method I starting from 128 (6.4 g). Purification by flash
chromatography, eluting with hexane/EtOAc (1:3), gave 1.14
g (15%) of 39: mp 198 °C; 1H NMR (DMSO) δ 2.31 (s, 3H),
2.44 (s, 3H), 3.27 (s, 3H), 6.47 (s, 1H), 6.72 (d, J ) 9.0 Hz,
1H), 7.07 (d, J ) 9.0 Hz, 1H), 7.32 (s, 1H), 8.08 (s, 4H). HPLC
purity (method 1): 97.6%.
3-(2-Ch lor o-4-m et h oxyp h en oxy)-2-(4-m et h a n esu lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (40) was prepared accord-
ing to method I starting from 129 (2.0 g). Purification by flash
chromatography, eluting with hexane/EtOAc (3:7), gave 0.18
g (8%) of 40: mp 171-172 °C; 1H NMR (CDCl3) δ 2.45 (s, 3H),
3.08 (s, 3H), 3.74 (s, 3H), 6.34 (s, 1H), 6.64 (s, 2H), 6.97 (s,
1H), 8.02 (d, J ) 8.7 Hz, 2H), 8.16 (d, J ) 8.7 Hz, 2H). HPLC
purity (method 1): 98.2%.
1
6.54 (s, 1H), 7.25 (dd, J ) 6.9, 2.1 Hz, 2H), 8.06 (m, 4H), 8.20
(dd, J ) 6.9, 2.1 Hz, 2H). HPLC purity (method 1): 99.4%.
4-[2-(4-Meth a n esu lfon ylp h en yl)-6-m eth yl-4-oxo-4H-p y-
r a n -3-yloxy]ben zoic a cid m eth yl ester (30) was prepared
according to method I starting from 121 (2.38 g). Purification
by flash chromatography, eluting with hexane/EtOAc (1:1),
gave 0.8 g (28%) of 30: mp 219 °C; 1H NMR (CDCl3) δ 2.47 (s,
3H), 3.07 (s, 3H), 3.88 (s, 3H), 6.39 (s, 1H), 6.98 (d, J ) 8.7
Hz, 2H), 7.98-8.07 (m, 6H). HPLC purity (method 1): 99.2%.
3-(2,4-Diflu or op h en oxy)-2-(4-m eth a n esu lfon ylp h en yl)-
6-m eth ylp yr a n -4-on e (31) was prepared according to method
H starting from 111 (18.5 g). Purification by flash chromatog-
raphy with silica gel, eluting with and ethyl hexane/EtOAc
(1:1), gave 9.96 g (22%) of 31: mp 196-197 °C; 1H NMR
(DMSO) δ 2.44 (s, 3H), 3.26 (s, 3H), 6.48 (s, 1H), 6.89-6.98
(m, 1H), 7.04-7.14 (m, 1H), 7.34-7.44 (m, 1H), 8.09 (s, 4H).
HPLC purity (method 1): 99.5%. Anal. (C19H14F2O5S) C, H,
S.
5.5. Syn th esis of P yr on es 41-47. 3-P h en oxy-2-(4-m eth -
a n esu lfon ylp h en yl)-6-m eth ylp yr a n -4-on e (41). A mixture
of 0.2 g (0.45 mmol) of compound 24, 0.5 g (6.7 mmol) of sodium
formate, 26 mg (0.02 mmol) of tetrakis(triphenylphosphine)-
palladium(0), and 2 mL of DMF was heated at 100 °C for 16
h. Then the mixture was poured into water and extracted with
EtOAc. The organic solution was dried, and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography, eluting with hexane/EtOAc (1:1), to give
3-(3,4-Diflu or op h en oxy)-2-(4-m eth a n esu lfon ylp h en yl)-
6-m eth ylp yr a n -4-on e (32) was prepared according to method
H starting from 112 (2.68 g). Purification by flash chromatog-
raphy, eluting with hexane/EtOAc (1:1), gave 0.38 g (12%) of
1
32: mp 194 °C; H NMR (DMSO) δ 2.42 (s, 3H), 3.26 (s, 3H),
1
0.05 g (30%) of pure 41: mp 169 °C; H NMR (DMSO) δ 2.44
6.48 (s, 1H), 6.86 (m, 1H), 7.24 (m, 1H), 7.36 (dd, J ) 18.0,
10.8 Hz, 1H), 8.05 (m, 4H). HPLC purity (method 1): 98.9%.
3-(3,4-Dich lor op h en oxy)-2-(4-m eth a n esu lfon ylp h en yl)-
6-m eth ylp yr a n -4-on e (33) was prepared according to method
H starting from 122 (4.9 g). Purification by flash chromatog-
raphy, eluting with hexane/EtOAc (3:2), gave 0.30 g (5%) of
(s, 3H), 3.25 (s, 3H), 6.47 (s, 1H) 6.95-7.04 (m, 2H), 7.29 (m,
1H), 8.07 (m, 4H). HPLC purity (method 1): 98.3%. Anal.
(C19H16O5S) C, H, S.
Gen er a l P r oced u r e for th e Syn th esis of P yr on es 42-
45. Meth od J . 2-(4-Meth a n esu lfon ylp h en yl)-6-m eth yl-3-
(2-m eth ylp h en oxy)p yr a n -4-on e (42). To a solution of 1.4 g
(0.032 mol) of 22 in 15 mL of DMF was added 43 mg (0.19
mmol) of palladium acetate, 0.23 g (0.77 mmol) of tri-o-
tolylphosphine, 2.4 mL (0.017 mol) of tetramethyltin, and 1.45
mL (0.10 mol) of triethylamine. The mixture was heated to
100 °C during 4 days. After cooling, the reaction mixture was
filtered through Celite and water was added to the filtrate.
The aqueous phase was extracted with EtOAc, and the organic
layer was washed with brine, dried, and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography, eluting with hexane/EtOAc (1:2), to give 0.77 g (65%)
of compound 42: mp 168 °C; 1H NMR (DMSO) δ 2.32 (s, 3H),
2.44 (s, 3H), 3.26 (s, 3H), 6.46 (s, 1H), 6.65 (d, J ) 7.5 Hz,
1H), 6.92 (m, 1H), 7.02 (m, 1H), 7.22 (d, J ) 7.2 Hz, 1H), 8.06
(d, J ) 9.0 Hz, 2H), 8.11 (d, J ) 9.0 Hz, 2H). HPLC purity
(method 1): 98.2%.
1
33: mp 177 °C; H NMR (CDCl3) δ 2.44 (s, 3H), 3.28 (s, 3H),
6.48 (s, 1H), 7.07 (m, 1H), 7.40 (s, 1H), 7.56 (d, J ) 10.8 Hz,
1H), 8.08 (m, 4H). HPLC purity (method 1): 95.0%.
3-(4-Chloro-2-fluorophenoxy)-2-(4-methanesulfonylphen-
yl)-6-m eth ylp yr a n -4-on e (34) was prepared according to
method I starting from 123 (0.58 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2/5), gave 0.23
g (34%) of 34: mp 188-189 °C; 1H NMR (CDCl3) δ 2.45 (s,
3H), 3.09 (s, 3H), 6.35 (s, 1H), 6.80 (dd, J HH ) J HF ) 8.7 Hz,
1H), 6.97 (m, 1H), 7.15 (d, J ) 12.6 Hz, 1H), 8.04 (d, J ) 8.7
Hz, 2H), 8.11 (d, J ) 8.7 Hz, 2H). HPLC purity (method 1):
99.6%. Anal. (C19H14FClO5S) C, H, S.
3-(4-Bromo-2-fluorophenoxy)-2-(4-methanesulfonylphen-
yl)-6-m eth ylp yr a n -4-on e (35) was prepared according to
method I starting from 124 (2.30 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2:5), gave 1.3 g
(48%) of 35: mp 215 °C; 1H NMR (CDCl3) δ 2.45 (s, 3H), 3.08
(s, 3H), 6.34 (s, 1H), 6.74 (t, J ) 9.0 Hz, 1H), 7.12 (d, J ) 9.0
Hz, 1H), 7.29 (d, J ) 9.0 Hz, 1H), 8.04 (d, J ) 9.0 Hz, 2H),
8.10 (d, J ) 9.0 Hz, 2H). HPLC purity (method 1): 99.9%. Anal.
(C19H14FBrO5S) C, H, S.
3-(4-Bromo-2-chlorophenoxy)-2-(4-methanesulfonylphen-
yl)-6-m eth ylp yr a n -4-on e (36) was prepared according to
method I starting from 125 (2.18 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2:5), gave 1.09
g (43%) of 36: mp 214-215 °C; 1H NMR (CDCl3) δ 2.47 (s, 3H),
3.08 (s, 3H), 6.37 (s, 1H), 6.58 (d, J ) 8.5 Hz, 1H), 7.20 (d, J
) 8.5 Hz, 1H), 7.56 (s, 1H), 8.03 (d, J ) 7.5 Hz, 2H), 8.12 (d,
J ) 7.5 Hz, 2H). HPLC purity (method 1): 99.8%.
3-(4-F lu or o -2-m e t h y lp h e n o x y )-2-(4-m e t h a n e su lfo -
n ylp h en yl)-6-m eth ylp yr a n -4-on e (37) was prepared accord-
ing to method I starting from 126 (11.15 g). Purification by
flash chromatography, eluting with hexane/EtOAc (1:3), gave
2.2 g (16%) of 37: mp 146 °C; 1H NMR (DMSO) δ 2.32 (s, 3H),
2.43 (s, 3H), 3.27 (s, 3H), 6.46 (s, 1H), 6.69-6.72 (m, 1H), 6.83-
6.86 (m, 1H), 7.10-7.13 (m, 1H), 8.09 (s, 4H). HPLC purity
(method 1): 96.7%.
3-(2-Ch lor o-4-m e t h ylp h e n oxy)-2-(4-m e t h a n e su lfo-
n ylp h en yl)-6-m eth ylp yr a n -4-on e (38) was prepared accord-
ing to method I starting from 127 (10.01 g). Purification by
flash chromatography, eluting with hexane/EtOAc (1:1), gave
3.3 g (28%) of 38: mp 159 °C; 1H NMR (DMSO) δ 2.23 (s, 3H),
2.44 (s, 3H), 3.27 (s, 3H), 6.48 (s, 1H), 6.81 (d, J ) 8.7 Hz,
1H), 6.98 (d, J ) 8.7 Hz, 1H), 7.32 (s, 1H), 8.07 (s, 4H). HPLC
purity (method 1): 98.9%.
2-(4-Meth an esu lfon ylph en yl)-6-m eth yl-3-(3-m eth ylph e-
n oxy)p yr a n -4-on e (43) was prepared according to method J
starting from 23 (1.15 g). Recrystallization from EtOH/water
(1:2) gave 0.28 g (29%) of 43: mp 162 °C; 1H NMR (DMSO) δ
2.25 (s, 3H), 2.44 (s, 3H), 3.26 (s, 3H), 6.46 (s, 1H), 6.73-6.85
(m, 3H), 7.13-7.19 (m, 1H), 8.07 (s, 4H). HPLC purity (method
1): 95.0%.
2-(4-Meth a n esu lfon ylp h en yl)-3-(4-m eth ylp h en oxy)-6-
m eth ylp yr a n -4-on e (44) was prepared according to method
J starting from 24 (0.16 g). Purification by flash chromatog-
raphy, eluting with hexane/EtOAc (2:3), gave 0.052 g (47%) of
1
44: mp 185 °C; H NMR (DMSO) δ 2.22 (s, 3H), 2.43 (s, 3H),
3.26 (s, 3H), 6.46 (s, 1H), 6.85 (d, J ) 8.4 Hz, 2H), 7.08 (d, J
) 8.4 Hz, 2H), 8.06 (m, 4H). HPLC purity (method 1): 98.5%.
Anal. (C20H18O5S) C, H, S.
3-(2-F lu or o -4-m e t h ylp h e n o xy )-2-(4-m e t h a n e su lfo -
n ylp h en yl)-6-m eth ylp yr a n -4-on e (45) was prepared accord-
ing to method J starting from 35 (0.83 g). Purification by flash
chromatography, eluting with hexane/EtOAc (2:3), gave 0.45
1
g (64%) of 45: mp 171 °C; H NMR (DMSO) δ 2.24 (s, 3H),
2.43 (s, 3H), 3.27 (s, 3H), 6.47 (s, 1H), 6.83-6.90 (m, 2H), 7.12
(d, J ) 12.0 Hz, 1H), 8.08 (s, 4H). HPLC purity (method 1):
99.6%.
3-(4-Am in op h en oxy)-2-(4-m et h a n esu lfon ylp h en yl)-6-
m eth ylp yr a n -4-on e (46). To a solution of 0.5 g (1.25 mmol)
of compound 29 in 2 mL of EtOH/water (1:1) was added 0.21
g (3.7 mmol) of iron, and the mixture was heated to reflux for
20 min. After the mixture was cooled, 0.22 mL of HCl(conc)
dissolved in 2 mL of EtOH/water (1:1) was added slowly and

3886 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 15
Caturla et al.
Knockout Mice by Inhibition of Cyclooxygenase 2 (COX-2). Cell
1996, 87 (5), 803-809.
the resulting mixture was refluxed for 2 h. After the mixture
was cooled, active charcoal and more EtOH/water (1:1) were
added with stirring and the mixture was filtered through
Celite. The filtrate was concentrated under reduced pressure
and the residue was purified by flash chromatography, eluting
with CH2Cl2/MeOH (93:7), to give 0.16 g (35%) of compound
(8) Singh, B.; Lucci, A. Role of Cyclooxygenase-2 in Breast Cancer.
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Koboldt, C. M.; Masferrer, J . L.; Perkins, W. E.; Rogers, R. S.;
Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. 4-[5-
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1
46: mp 212-213 °C; H NMR (CDCl3) δ 2.44 (s, 3H), 3.07 (s,
3H), 6.34 (s, 1H), 6.60 (d, J ) 8.7 Hz, 2H), 6.77 (d, J ) 8.7 Hz,
2H), 7.99 (d, J ) 8.4 Hz, 2H), 8.10 (d, J ) 8.4 Hz, 2H). HPLC
purity (method 1): 95.3%.
4-[2-(4-Meth a n esu lfon ylp h en yl)-6-m eth yl-4-oxo-4H-p y-
r a n -3-yloxy]ben zoic Acid (47). To a solution of 0.1 g (0.24
mmol) of compound 30 in 3 mL of dioxane were added 2.5 mL
of water and 2.5 mL of HCl(conc). The mixture was heated to
reflux for 5 h. After the mixture was cooled, water was added
and the aqueous phase was extracted with EtOAc. The organic
layer was washed with water and brine, dried, and concen-
trated to give a residue that was recrystallized from diethyl
ether affording 0.082 g (85%) of compound 47: mp 268-269
°C; 1H NMR (DMSO) δ 2.45 (s, 3H), 3.26 (s, 3H), 6.51 (s, 1H),
7.08 (d, J ) 8.7 Hz, 2H), 7.88 (d, J ) 8.7 Hz, 2H), 8.06 (s, 4H),
12.80 (bs, 1H). HPLC purity (method 1): 99.4%.
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Su p p or tin g In for m a tion Ava ila ble: Elemental analysis
data for the compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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J M049882T