A convenient synthesis of the key intermediate of selective COX-2 inhibitor Etoricoxib

Article abstract of DOI:10.1039/c3ra42619j

An original strategy for the synthesis of ketone 1, the key intermediate for preparing Etoricoxib, an important nonsteroidal anti-inflammatory drug, has been developed. Inexpensive 5-hydroxy-2-methylpyridine was converted to the corresponding acetyl derivative in four practical synthetic steps. The following palladium-catalyzed α-arylation of acetylpicoline with 4-bromo- or 4-chlorophenyl methyl sulfone was efficiently optimized in order to afford ketone 1 in remarkable yield.

Full text of DOI:10.1039/c3ra42619j

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A convenient synthesis of the key intermediate of
selective COX-2 inhibitor Etoricoxib3
Cite this: RSC Advances, 2013, 3,
18544
Stefano Tartaggia,*a Andrea Caporale,a Francesco Fontana,b Paolo Stabile,b
Andrea Castellinb and Ottorino De Lucchia
An original strategy for the synthesis of ketone 1, the key intermediate for preparing Etoricoxib, an
important nonsteroidal anti-inflammatory drug, has been developed. Inexpensive 5-hydroxy-2-methylpyr-
idine was converted to the corresponding acetyl derivative in four practical synthetic steps. The following
palladium-catalyzed a-arylation of acetylpicoline with 4-bromo- or 4-chlorophenyl methyl sulfone was
efficiently optimized in order to afford ketone 1 in remarkable yield.
Received 29th May 2013,
Accepted 29th July 2013
DOI: 10.1039/c3ra42619j
www.rsc.org/advances
`
Among different types of NSAIDs, Dube et al. demonstrated
Introduction
that 2-pyridinyl-3-(4-methylsulfonyl)phenylpyridines are
potent and selective COX-2 inhibitors7 and Etoricoxib (3)
represents one of the most specific drug within this class,
exhibiting 106-fold selectivity for inhibition of COX-2 over
COX-1.8
Etoricoxib is approved in Europe (brand name Arcoxia) to
treat patients with osteoarthritis, rheumatoid arthritis, anky-
losing spondylitis and acute gouty arthritis.9
Early synthetic strategies to access Etoricoxib and other
diaryl pyridines were based on the connection of aryl groups to
the central Cl-pyridine ring of 3 through the palladium
catalyzed cross-coupling reaction of pyridine halides with
arylboronic acids, arylboronates or arylstannanes as organo-
metallic partners.7
More recently, Davies described the construction of the
central pyridine ring of Etoricoxib through the efficient
annulation of the readily accessible ketone 1 with the
inexpensive vinamidinium specie 2 (CDT-phosphate), followed
by treatment with ammonia.10 This process, that combines a
great efficiency with the use of inexpensive reagents, has been
also adopted for the manufacturing of Etoricoxib on an
industrial scale.11
The control of pain and inflammation occurring in chronic
illnesses, such as osteoarthritis, inflammatory arthropathies,
metastatic bone pain, postoperative pain or rheumatoid
arthritis,1 led to the widespread use of specific anti-inflam-
matory drugs. Most nonsteroidal anti-inflammatory drugs
(NSAIDs) act by the nonselective inhibition of the enzyme
cyclooxygenase (COX), including both the cyclooxygenase-1
(COX-1) and cyclooxygenase-2 (COX-2) isoenzymes, which are
involved in the biosynthesis of prostaglandins, prostacyclins,
and thromboxanes from arachidonic acid.2 The chronic use of
nonselective COX-1/COX-2 inhibitors (such as aspirin, ibupro-
fen, and naproxen) is often associated with gastro-intestinal
problems such as ulcers or duodenum internal bleeding,3
including also other side-effects for kidneys, platelets and
lungs.4
These adverse effects have been correlated to the inhibition
of COX-1, which plays an important role in regulating many
normal physiological processes, for example in the stomach
lining where prostaglandins serve a protecting role against
gastric mucosal damages. On the other hand, COX-2 is the
enzyme expressed during the inflammation process and is
responsible for the proinflammatory prostanoid production.5
Therefore, the specific inhibition of COX-2 would greatly
improve the gastrointestinal safety profile by reducing the
class-typical adverse effects of traditional NSAIDs.6
In this context, extensive efforts have been devoted to the
design of new and efficient synthetic strategies to ketosulfone
1, which is consequently the key intermediate for the synthesis
of Etoricoxib.
Three main approaches to the synthesis of 1 starting from
methyl 6-methylnicotinate (7) were previously described by
Davies (Scheme 2).10a In the first strategy, N,P acetal 5,
obtained from nicotinaldehyde 4, was reacted with 4-metha-
nesulfonylbenzaldehyde (6) to provide the desired ketosulfone
1 (path a, 65% overall yield). Alternatively, methyl nicotinate 7
was treated with carboxylic acid 8 in the presence of an excess
of tBuMgCl to prepare compound 1 in one step (path b, 58%
yield). The Grignard approach was applied also to Weinreb
a
`
Universita Ca’ Foscari di Venezia, Dipartimento di Scienze Molecolari e
Nanosistemi, Dorsoduro 2137, I-30123 Venice, Italy.
E-mail: stefano.tartaggia@unive.it; Fax: +39-41-2348517; Tel: +39-41-2348515
bF.I.S. – Fabbrica Italiana Sintetici S.p.A. Alte di Montecchio Maggiore (Vicenza), Via
Milano, 26, I-36075 Vicenza, Italy
Electronic supplementary information (ESI) available: Experimental
3
procedures and 1H and 13C NMR spectra for all compounds. See DOI: 10.1039/
c3ra42619j
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Scheme 1 Synthesis of Etoricoxib (3) from ketone 1 and CDT-phosphate (2).
amide 9, which was firstly coupled with thioether 10 to obtain
the intermediate 11 and finally converted to sulfone 1, after an
additional oxidation step (path c, 68% overall yield).
Although the latter approach has been improved and
implemented for the industrial synthesis of Etoricoxib,12 the
main drawback of such a process is the oxidation from sulfide
to sulfone before the annulation of 1 with CDT-phosphate (2)
(Scheme 1).
Successful oxidation methodologies included the use of
aqueous hydrogen peroxide10a as well as combination of
peracetic acid and hydrogen peroxide as the oxidants in acid
media and in the presence of sodium tungstate as the
oxidation catalyst.13 However, the possible formation of
undesired sulfoxide and N-oxide byproducts and the purifica-
tion of the final product from pollutant tungstate are common
problems associated with the oxidation process.
Scheme 3 Synthetic strategies for the preparation of ketosulfone
ethynylpicoline 12.
1 from
sulfone 13a and
a derivative of 2-methylpiridine. Two
strategies were planned at the outset: (a) Sonogashira coupling
of ethynylpicoline 12 with 4-bromo- or 4-chlorophenyl methyl
sulfone (13a and 13b respectively), followed by the hydration
of the disubstituted alkyne 15 to the desired product 1, or (b)
hydration of 12 to acetylpicoline 14 to be coupled via
palladium-catalyzed a-arylation with sulfones 13a or 13b, as
outlined in Scheme 3.
In both strategies, ethynylpicoline 12 was the key inter-
mediate to obtain the final product 1, in substitution of
original nicotinal derivatives reported by Davies.10a 5-Hydroxy-
2-methylpyridine (16) was therefore chosen as inexpensive and
easily available starting material14 and was firstly converted to
the corresponding trifluoromethanesulfonate derivative (17)
by treatment with triflic anhydride in pyridine.15
Herein we report
a new and efficient synthesis of
ketosulfone 1 starting from a 2-methylpiridine (picoline)
derivative instead of methyl 6-methylnicotinate, as previously
reported. We designed an original strategy in five synthetic
steps, which were efficiently optimized in order to prepare
ketosulfone 1 in high yield.
The subsequent Pd-catalyzed coupling of picoline triflate
(17) with 2-methyl-but-3-yn-2-ol afforded 2-methyl-4-(6-methyl-
pyridin-3-yl)-but-3-yn-2-ol (18).
Results and discussion
The optimal reaction conditions to efficiently perform this
step were determined through a screening study by using
different solvents, bases, and ligands as summarized in
Table 1.
The new synthetic approach to ketosulfone 1 was based on the
building of a new C–C bond between 4-bromophenyl methyl
After testing different solvents, the use of a 1 : 1 NMP–
toluene mixture provided the best option (entry 4) with respect
to toluene, NMP or THF when used alone. The influence of
different bases was also investigated, observing that DABCO
and piperidine were the most effective for the reaction (entries
5 and 6). Finally, replacing PPh3 with P(p-tol)3 as a ligand for
the palladium catalyst resulted in 93% yield of product 18
Scheme 4 Synthesis of ethynylpicoline 12. Reagents and conditions: (i) Tf2O,
pyridine, 92%; (ii) 2-methyl-but-3-yn-2-ol, Pd(OAc)2, P(p-tol)3, piperidine, 91%;
(iii) NaOH, toluene, reflux, 90%.
Scheme 2 Reported synthetic approaches to ketosulfone 1, a key intermediate
for the preparation of Etoricoxib 3.10a
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Table 1 Synthesis of 2-methyl-4-(6-methyl-pyridin-3-yl)-but-3-yn-2-ol (18) from
triflate 17 and 2-methyl-3-butyn-2-ola
Entry
Solvent
Base
Ligand
Yield [%]
1
2
3
4
5
6
7
THF
NMP
Toluene
Toluene/NMP
Toluene/NMP
Toluene/NMP
Toluene/NMP
NEt3
NEt3
NEt3
NEt3
DABCO
piperidine
piperidine
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
P(p-tol)3
5
11
24
31
86
87
93
a
Reaction conditions: 17 (1 mmol), 2-methyl-but-3-yn-2-ol (1.2
mmol), Pd(OAc)2 (2 mol%), ligand (4 mol%), base (3 mmol), 16 h, 40
uC. Yields were determined by GC using tetradecane as an internal
standard.
Scheme 5 Coupling of ethynylpicoline 12 with 4-bromophenyl methyl sulfone
(13a) and hydration experiments of the corresponding alkyne 15.
reaction conditions in order to maximize the yield of
ketosulfone 1 was performed (Table 2).
(entry 7) by carrying out the reaction under very mild
conditions (40 uC for 16 h).
Early experiments, carried out in THF in the presence of
Pd(OAc)2 and PPh3 as the catalytic system, showed that
acetylpicoline decomposes when combined with strong bases
such as sodium or potassium tert-butoxide. Changing the base
to K3PO4 allowed to obtain product 1 in 25% yield (Entry 4).
The reaction was further optimized by modifying the catalyst
with different ligands. In fact, simple monodentate phos-
phines displayed a limited efficiency for this reaction, whereas
bidentate ligand 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene (Xantphos) proved to be the best ligand for this
coupling process, leading to 46% yield (Entry 7). A decisive
improvement was obtained by carrying out the reaction in
NMP (58%, Entry 8) instead of THF, which is in contrast with
previously reported a-arylation couplings successfully per-
formed in less polar media.24 Raising the temperature to 100
uC led also to a positive impact on the reaction, by providing
product 1 in 75% yield (Entry 9). A change of the palladium
source to Pd(acac)2 was beneficial thereto (88% yield, Entry
14), whereas other precursors had a detrimental effect on the
yield of this process.
Varying the metal–ligand ratio from 1 : 1 to 1 : 2 deter-
mined a further breakthrough for the reaction, by implement-
ing the product yield to 94% (Entry 15). This was found also to
be crucial in order to perform the synthesis of 1 in high yield
with a reduced amount of palladium to 0.5 mol% (Scheme 7).
The a-arylation of acetylpicoline 14 was finally investigated
with 4-chlorophenyl methyl sulfone (13b). The substitution of
bromo with chloro on phenylmethyl sulfone dramatically
reduced the yield from 94% to 26% under the same reaction
conditions adopted for 13a. However, replacing the solvent
The scale-up of the reaction from 1 to 30 mmol allowed to
prepare 2-methyl-4-(6-methyl-pyridin-3-yl)-but-3-yn-2-ol (18) in
91% yield with a reduced amount of Pd to 1 mol%. The
following deprotection step was carried out without isolation
of intermediate 18 with NaOH in refluxing toluene for 2 h,
obtaining the desired product by sublimation from the crude
reaction mixture. The overall yield of ethynylpicoline 12 was
82% from triflate 17 (Scheme 4).
Synthesis of ketosulfone 1
The preparation of ketosulfone 1 from ethynylpicoline 12 was
firstly investigated according to Scheme 3, path a. The Pd/Cu-
catalyzed coupling of 12 with 4-bromophenyl methyl sulfone
(13a)16 afforded the disubstituted acetylene 15 in 78%.
Unfortunately, the following metal catalyzed alkyne hydration
in the attempt to prepare 1, which included the use of several
Pt,17 Pd,18 Ru19 and Au20 catalysts, did not show appreciable
conversion of 15 to 1. Titanium hydroamination21 as well as
acid catalyzed hydration22 reactions resulted also ineffective
when applied to alkyne 15, likely because the substrate is too
electrophilic to interact with metals or acids in catalytic
amounts.
Instead, hydration of 15 was successful when strong acid
conditions were applied. In fact, treating alkyne 15 with a 4 : 1
H2SO4–toluene mixture at 80 uC23 led quantitatively to
ketosulfone 19 within three hours (Scheme 5). Unfortunately,
only the undesired regioisomeric product was recovered.
Compound 19 cannot provide Etoricoxib (3) because the
eventual reaction with CDT-phosphate would lead to a
pyridine ring with the nitrogen on the opposite side to the
picoline group.
On the other hand, the hydration of ethynylpicoline 12
under the same acidic conditions applied for 15 led to
acetylpicoline 14 with Markovnikov selectivity in 92% yield
(Scheme 6).
Acetylpicoline was subsequently used as starting material
for preparing ketosulfone 1 through the Pd-catalyzed a-aryla-
tion24 with 4-bromophenyl methyl sulfone (13a) according to
Scheme 3, path b. Therefore, a screening of the optimal
Scheme 6 Hydration of ethynylpicoline and reaction with 4-bromophenyl
methyl sulfone to obtain ketosulfone 1.
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similar global yield was obtained, the strategy presented here
provided an appreciable improvement on the original pub-
lished routes to ketone 1. In fact, picoline derivative 16 was
found a more convenient starting material than methyl
nicotinate 714 and the use of stoichiometric organometallic
reagents was avoided. Moreover, the Pd-catalyzed a-arylation
did not present a significant formation by-products, which is
highly desirable for the synthesis of active pharmaceutical
ingredients.
Table 2 Pd-catalyzed coupling between acetylpicoline 14 and 4-bromophenyl
methyl sulfone (13a)a
Entry Solvent Pd
Ligand [mol%] Base
T/uC Yield [%]
1
2
toluene Pd(OAc)2
dioxane Pd(OAc)2
PPh3 (4)
PPh3 (4)
tBuOK 80
tBuOK 80
2
4
3
4
5
6
7
8
9
10
11
12
13
14
15
THF
THF
THF
THF
THF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3 (4)
PPh3 (4)
tBuOK 80
K3PO4 80
K3PO4 80
K3PO4 80
K3PO4 80
K3PO4 80
K3PO4 100 75
K3PO4 100 49
K3PO4 100 44
K3PO4 100 76
K3PO4 100 29
K3PO4 100 88
K3PO4 100 94
7
25
5
8
46
58
P(tBu)3 (4)
P(Cy)3 (4)
xantphos (2)
xantphos (2)
xantphos (2)
dppe (2)
Conclusions
xantphos (2)
(PdallylCl)2 xantphos (2)
Summarizing, a new synthetic strategy for preparing a key
intermediate of Etoricoxib has been developed. Inexpensive
5-hydroxypicoline was easily converted to the corresponding
acetylpicoline, which was finally coupled with 4-bromophenyl
methyl sulfone or 4-chlorophenyl methyl sulfone to obtain the
target compound 1 in high yield. In this approach two
palladium catalyzed coupling reactions were efficiently opti-
mized in order to use the lowest possible catalyst amount.
Moreover, exploiting the a-arylation strategy, ketosulfone 1
was prepared using a 2-methylpyridine derivative as starting
material instead of previously reported methyl nicotinate
derivatives. Stoichiometric organometallic reagents or the
preparation of phosphorous ylides as well as oxidation steps
previously reported were avoided. Therefore, the convenience
of the overall process with respect to those previously reported
is considerably increased.
Pd2(dba)3
Pd(acac)2
Pd(acac)2
xantphos (2)
xantphos (2)
xantphos (4)
a
Reaction conditions: 14 (1 mmol), 13a (1.2 mmol), Pd source (2
mol%), base (3 mmol), 16 h. Yields were determined by GC using
tetradecane as an internal standard.
with DMSO and carrying out the reaction at a higher
temperature (150 uC) led to 69% yield of product
1
(Scheme 7). Interestingly, no double arylation of acetylpicoline
was observed in this process.
Target compound 1 was therefore prepared in five synthetic
steps with 65% overall yield from picoline derivative 16 and
86% from ethynylpicoline (12). In this novel strategy, simple
reagents and conditions were utilized to prepare acetylpicoline
(14) in four simple transformations, including the triflation of
the starting material, the coupling with 2-methyl-but-3-yn-2-ol,
a deprotection step and the alkyne hydration under acid
conditions. The final step involved the palladium-catalyzed
a-arylation with 4-bromo or 4-chlorophenyl methyl sulfone to
access ketone 1 in high isolated yield. In previously reported
methods, the same product was obtained in 58–68% overall
yield from methyl 6-methylnicotinate (7) (Scheme 2) and in
one case a stoichiometric Grignard reagent and sodium
tungstate, as an oxidation catalyst, were utilized. Although a
Experimental section
General
All reactions, if not stated otherwise, were performed in oven-
dried glassware under an argon atmosphere containing a
teflon-coated stirring bar and dry septum. Chemicals and
solvents were either purchased (puriss. p.A.) from commercial
suppliers or purified by standard techniques. All reactions
were monitored by GC using tetradecane as an internal
standard. Response factors of the products with regard to
tetradecane were obtained experimentally by analyzing known
quantities of the substances. GC analyses were carried out
using an HP-5 capillary column (Phenyl methyl siloxane, 30 m
6 320 6 0.25, 100/2.3-30-300/3, 2 min at 50 uC, heating rate 25
uC min21, 3 min at 250 uC). Column chromatography was
performed with 230–400 mesh silica-gel. NMR spectra were
obtained on a Bruker AVANCE 300 spectrometer (300 MHz)
using CDCl3 as solvent, 300 MHz and 75 MHz, respectively.
Mass spectral data were acquired on a Trace GC-MS 2000
ThermoQuest. Melting points were measured on a Bu¨chi 535.
Trifluoromethanesulfonic acid 2-methylpyridin-5-yl ester (17)
[CAS-No 111770-91-3]15
To a solution of 5-hydroxy-2-methylpyridine (10.0 g, 91.7
mmol) and pyridine (11.0 mL, 137.0 mmol) in DCM (100 mL),
trifluoromethanesulfonic anhydride (18.5 mL, 110.0 mmol)
was added dropwise at 0 uC. After stirring for 1.5 h, MeOH (2
Scheme 7 Optimized conditions for the synthesis of ketosulfone 1 via the Pd-
catalyzed a-arylation of acetylpicoline 14 with sulfones 13a or 13b. Yields refer
to isolated products.
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mL) and saturated aqueous NaHCO3 (50 mL) were added to
the mixture. The organic layer was washed with brine (50 mL),
and dried over MgSO4. The solvent was removed in vacuum,
and the residue was distilled at reduced pressure (85 uC, 0.1
torr) to obtain trifluoromethanesulforic acid 6-methyl-pyridin-
3-yl ester as a colorless oil (20.3 g, 92% yield). 1H-NMR (300
MHz, CDC13): d = 8.44 (d, J = 2.8 Hz, 1 H), 7.49 (dd, J = 8.6, 2.9
Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 2.58 (s, 3 H) ppm; 13C-NMR
(75 MHz, CDC13): d = 159.0, 144.9, 141.8, 129.0, 124.2, 118.6 (q,
J = 320.4 Hz), 23.9 ppm; MS (70 eV), m/z (%): 241 (60) [M+], 108
(58), 80 (100), 69 (29), 53 (62).
CDC13): d = 158.7, 151.7, 139.9, 138.9, 132.3, 128.6, 127.4,
122.8, 116.3, 90.2, 90.0, 44.4, 24.6 ppm; MS (70 eV), m/z (%) 271
(100) [M+], 208 (48), 192 (48), 165 (26), 152 (11), 139 (9), 99 (7),
63 (9). Anal. Calcd for C15H13NO2S: C, 66.40; H, 4.83; N, 5.16.
Found: C, 66.48; H, 4.77; N, 5.25.
2-(6-Methylpyridin-3-yl)-1-(4-(methylsulfonyl)phenyl) ethanone
(19)26
2-Methyl-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridine (54.3
mg, 0.20 mmol) was dissolved in a toluene–H2SO4 mixture
(1 : 4, 2.5 mL) and stirred at 80 uC for 3 h. After cooling to rt,
the solution was neutralized with saturated aqueous NaHCO3
(20 mL) and extracted with EtOAc (3 6 20 mL). Combined
organic extracts were washed with H2O (20 mL), saturated
aqueous NaCl (20 mL), dried over MgSO4 and concentrated in
vacuum to afford the product 19 as a colourless solid (55.5 mg,
96% yield), mp 159–160 uC; 1H-NMR (300 MHz, CDC13): d =
8.39 (d, J = 1.8 Hz, 1 H), 8.17 (d, J = 8.8 Hz, 2 H), 8.05 (d, J = 8.8
Hz, 2 H), 7.48 (dd, J = 7.9, 2.2 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H),
4.29 (s, 2 H), 3.07 (s, 3 H), 2.54 (s, 3 H) ppm; 13C-NMR (75 MHz,
CDC13): d = 195.5, 157.5, 149.7, 144.5 140.2, 137.4, 129.3,
127.9, 126.0, 123.2, 44.2, 42.5, 24.0 ppm; MS (70 eV), m/z (%)
289 (13) [M+], 183 (100), 121 (35), 106 (18), 77 (17), 50 (4).
5-Ethynyl-2-methylpyridine (12) [CAS-No 1945-85-3]25
An oven-dried vessel equipped with a magnetic stirring bar
was charged with tri(p-tolyl)phosphine (176 mg, 0.58 mmol),
Pd(OAc)2 (65.0 mg, 0.29 mmol) and 6-methylpyridin-3-yl
trifluoromethanesulfonate (5.0 mL, 29.0 mmol). After purging
the vessel with alternating vacuum and Argon cycles, a
degassed solution of piperidine (11.0 mL, 117.4 mmol) in
NMP–toluene (1 : 1, 40 mL) was added. 2-Methyl-3-butyn-2-ol
(4.2 mL) was added via syringe and the mixture was stirred at
40 uC overnight. After cooling to rt, the mixture was diluted
with saturated aqueous NaHCO3 (80 mL) and extracted with
Et2O (3 6 50 mL). Combined organic extracts were washed
with H2O (20 mL), saturated aqueous NaCl (20 mL), dried over
MgSO4 and concentrated in vacuum. The crude product was
redissolved in dry toluene (100 mL) and finely crushed NaOH
(11.0 g, 275 mmol) was added. The mixture was heated to
reflux for few hours and monitored via TLC till the conversion
of 18 was complete. After filtration, the solution was washed
with saturated aqueous NaHCO3 (50 mL) and dried over
MgSO4. The solvent was removed under vacuum and the crude
product was purified by sublimation at reduced pressure to
3-Acetyl-6-methylpyridine (14) [CAS-No 36357-38-7]27
5-Ethynyl-2-methylpyridine (1.0 g, 8.5 mmol) was dissolved in
toluene and sulphuric acid (1 : 4, 10 mL) and heated at 80 uC
for 3 h. the solution was neutralized with saturated aqueous
NaHCO3 (30 mL) and extracted with AcOEt (3 6 30 mL).
Combined organic extracts were washed with H2O (20 mL),
saturated aqueous NaCl (20 mL), dried over MgSO4 and
concentrated in vacuum to afford the product 14 as a pale
1
yellow oil (1.06 g, 92% yield). H-NMR (300 MHz, CDC13): d =
1
8.96 (d, J = 1.8 Hz, 1 H), 8.04 (dd, J = 8.5, 2.4 Hz, 1 H), 7.18 (d, J
= 7.9 Hz, 1 H), 2.55 (s, 1 H), 2.55 (s, 3 H) ppm; 13C-NMR (75
MHz, CDC13): d = 196.4, 163.2, 149.5, 135.6, 129.8, 123.1, 26.5,
24.6 ppm; MS (70 eV), m/z (%) 135. (47) [M+], 120 (100), 92 (72),
65 (23), 43 (9).
obtain a colorless solid (2.79 g, 82% yield), mp 50–51 uC. H-
NMR (300 MHz, CDC13): d = 8.59 (d, J = 2.0 Hz, 1 H), 7.63 (dd, J
= 8.1, 2.2 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 3.15 (s, 1 H), 2.54 (s,
3 H) ppm; 13C-NMR (75 MHz, CDC13): d = 158.3, 152.1, 132.2,
122.6, 116.1, 80.6, 79.8, 24.4 ppm; MS (70 eV), m/z (%) 117.
(100) [M+], 89 (44), 63 (12), 50 (8).
1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl] ethanone
(1) [CAS-No 221615-75-4]10a
2-Methyl-5-((4-(methylsulfonyl)phenyl)ethynyl)pyridine (15)
An oven-dried vessel equipped with a magnetic stirring bar
was charged with triphenylphosphine (126 mg, 0.48 mmol),
Pd(OAc)2 (53.8 mg, 0.24 mmol), copper(I) iodide (60.8 mg, 0.32
mmol), 5-ethynyl-2-methylpyridine (1.87 g, 16.0 mmol) and
4-bromophenyl methyl sulfone (5.64 g, 24.0 mmol). After
purging the vessel with alternating vacuum and Argon cycles, a
degassed solution of piperidine (6.3 mL, 64 mmol) in toluene
(30 mL) was added and the mixture was stirred for 2 h at 60 uC.
After cooling to rt, the mixture was diluted with water (50 mL)
and extracted with AcOEt (3 6 50 mL). Combined organic
extracts were washed with H2O (20 mL), saturated aqueous
NaCl (20 mL), dried over MgSO4 and concentrated in vacuum.
The crude product was purified by silica gel chromatography
(eluant hexane–AcOEt in gradient from 8 : 2 to 2 : 8) affording
the product 15 (3.4 g, 78% yield) as a pale yellow solid, mp
An oven-dried vessel equipped with a magnetic stirring bar
and reflux condenser was charged with palladium(II) acetyla-
cetonate (30.5 mg, 0.1 mmol), 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (116 mg, 0.2 mmol), 4-bromophenyl methyl
sulfone (5.64 g, 24 mmol), 1-(6-methyl pyridine-3-yl) ethanone
(2.70 g, 20 mmol) and K3PO4 (12.7 g, 60.0 mmol). After purging
the vessel with alternating vacuum and argon cycles, dry and
degassed NMP (60 mL) was added and the mixture was stirred
at 100 uC for 16 h. After cooling to rt the mixture was diluted
with water (50 mL) and extracted with AcOEt (4 6 50 mL).
Combined organic extracts were washed with H2O (50 mL),
saturated aqueous NaCl (20 mL), dried over MgSO4 and
concentrated in vacuum. The crude product was purified by
silica gel chromatography (eluant hexane–AcOEt in gradient
from 5 : 5 to 0 : 10) affording the product 1 as a colorless solid
(5.38 g, 93% yield), mp 172–173 uC.
1
154–155 uC; H-NMR (300 MHz, CDC13): d = 8.67 (d, J = 2.2, 1
H), 7.93 (d, J = 8.2, Hz, 2 H), 7.69–7.74 (m, 3 H), 7.18 (d, J = 8.3
Alternatively, product 1 was prepared as follows: an oven-
dried vessel equipped with a magnetic stirring bar and reflux
Hz, 1 H), 3.07 (s, 3 H), 2.59 (s, 3 H) ppm; 13C-NMR (75 MHz,
18548 | RSC Adv., 2013, 3, 18544–18549
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W. Rodger, M. Greisser, A. W. Ford-Hutchinson, R. N. Young
and C. C. Chan, Pharmacol Exp Ther, 2001, 296, 558; (b) W.
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condenser was charged with palladium(II) acetylacetonate
(15.2 mg, 0.05 mmol), 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (30.5 mg, 0.1 mmol), 4-chlorophenyl methyl
sulfone (2.10 g, 11 mmol), 1-(6-methyl pyridine-3-yl) ethanone
(1.35 g, 10.0 mmol) and K3PO4 (6.36 g, 30.0 mmol). After
purging the vessel with alternating vacuum and argon cycles,
dry and degassed DMSO (20 mL) was added and the mixture
was stirred at 150 uC for 16 h. Work up and purification were
carried out as described above. Product 1 was obtained as a
9 K. F. Croom and M. A. A. Siddiqui, Drugs, 2009, 69, 1513.
10 (a) W. I. Davies, J. F. Marcoux, E. G. Corley, M. Journet, D.
W. Cai, M. Palucki, J. Wu, R. D. Larsen, K. Rossen, P. J. Pye,
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1
colourless solid (1.98 g, 69% yield), mp 172–173 uC; H-NMR
(300 MHz, CDC13): d = 9.13 (d, J = 2.2, 1 H), 8.17 (dd, J = 8.2, 2.4
Hz, 1 H), 7.92 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.30
(d, J = 7.9 Hz, 1 H), 4.39 (s, 2 H), 3.05 (s, 3 H), 2.65 (s, 3 H) ppm;
13C-NMR (75 MHz, CDC13): d = 194.8, 163.9, 149.4, 140.1 139.3,
136.1, 130.6, 129.1, 127.7, 123.6, 45.1, 44.5, 24.7 ppm; MS (70
eV), m/z (%) 289 (0.1) [M+], 120 (100), 92 (28), 65 (13), 39 (3).
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Acknowledgements
We gratefully acknowledge MIUR (Ministero dell’Istruzione,
`
dell’Universita e della Ricerca – Roma within the national
PRIN framework) and F.I.S. for financial supporting.
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