A novel three-step synthesis of Celecoxib via palladium-catalyzed direct arylation

Article abstract of DOI:10.1016/j.tetlet.2011.08.174

A novel three linear step synthesis of Celecoxib was achieved in 33% overall yield via a key regioselective direct C-H arylation reaction between a 1,3-disubstituted pyrazole and an aryl bromide.

Full text of DOI:10.1016/j.tetlet.2011.08.174

Tetrahedron Letters 52 (2011) 6000–6002
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel three-step synthesis of Celecoxib via palladium-catalyzed direct
arylation
⇑
Steven M. Gaulier , Reuben McKay, Nigel A. Swain
World Wide Medicinal Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel three linear step synthesis of Celecoxib was achieved in 33% overall yield via a key regioselective
direct C–H arylation reaction between a 1,3-disubstituted pyrazole and an aryl bromide.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 March 2011
Revised 12 August 2011
Accepted 30 August 2011
Available online 5 September 2011
Keywords:
Direct arylation
Celecoxib
Pd catalysis
Celecoxib (1) (Celebrex™) is a non steroidal anti-inflammatory
drug used for the treatment of numerous diseases and medical
conditions including osteoarthritis, rheumatoid arthritis, acute
pain, painful menstruation, and menstrual symptoms.1 This phar-
maceutical agent exerts its pharmacological effect as a highly
selective cyclooxygenase (COX-2) inhibitor.
1,3-disubstitution pattern. In addition, the pyrazole moiety could
represent a challenge regarding the regioselectivity of the aryla-
tion.8 With this in mind, we felt Celecoxib presented an exciting
and relevant challenge to explore direct C–H arylation methodolo-
gies and further expand the scope, as well as the regioselectivity, of
this transformation on a novel pyrazole moiety. Our retrosynthetic
approach consisted of a regioselective C5–C–H arylation following
selective N1-arylation of a trifluoromethyl pyrazole (Scheme 2).
Our synthetic plan was to start with the commercially available
3-(trifluoromethyl)-1H-pyrazole (6) which was reacted under reg-
ioselective N-arylation conditions with commercial 4-iodoben-
zenesulfonamide. Despite various efforts, the coupling reaction
was poor-yielding, not reproducible and the product proved diffi-
cult to isolate. We, therefore, opted for a protecting group strategy
on the sulfonamide functionality and selected a dibenzyl group9
because of the commercial accessibility of the starting amine and
the simplicity of the deprotection protocol (Scheme 3).
The sulfonamide coupling between pipsyl chloride (7) and
dibenzylamine took place in high yield to afford the sulfonamide 8.
Intermediate 8 was then treated with trifluoromethyl pyrazole
6 under standard Ullmann conditions,10 switching the solvent from
toluene to 1,4-dioxane to enhance solubility. Pyrazole intermediate
9 was obtained in good yield without the use of chromatography
and the regioselectivity of the N-arylation was confirmed by
NMR experiments11 (NOESY and 13C NMR).
A few processes have been described in the literature to synthe-
size Celecoxib. The commercial route consists of a condensation
reaction between diketone intermediate
3
and 4-sul-
famidophenylhydrazine 2 (Scheme 1). However, the lack of regi-
oselectivity with this method can result in a complex mixture of
pyrazole regioisomers, which can be difficult to purify.2 A more re-
cent method to minimize the regiocontrol problems has been
described by carefully selecting the appropriate solvents and con-
ditions (ethyl acetate and water at reflux).3 In another strategy,
hydrazine 2 is added via a Michael addition to butynone 4, which
subsequently cyclises to give the desired pyrazole, avoiding any
regioselective issue.4 Finally, Oh reported recently that hydrazo-
noyl sulfonate 5 undergoes 1,3 dipolar cycloaddition reactions
with an enamine to generate Celecoxib in good yield.5
The recent expansion of research into direct arylation of hetero-
cycles6 prompted us to explore whether this method could be ap-
plied toward the synthesis of drug-like molecules. Although
poorly represented as a heterocycle, several groups have recently
published robust intramolecular and intermolecular direct aryla-
tion protocols on pyrazoles.7 However, none of the substrates con-
tained the crucial trifluoromethyl functional group or the required
With the intermediate 9 in hand, we carefully selected the reac-
tion conditions to carry out the direct C–H arylation. We envisaged
several potential sets of conditions, each of them representative of
a different mechanism for the transformation. We believed the
Concerted Metallation Deprotonation (CMD) conditions first re-
ported by both Fagnou’s12 and Echevaren’s13 groups and later
⇑
Corresponding author. Tel.: +44 1304 642 624.
E-mail addresses: stevengaulier@voila.fr, steven.gaulier@pfizer.com (S.M. Gau
lier).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.174

S. M. Gaulier et al. / Tetrahedron Letters 52 (2011) 6000–6002
6001
O
O
condensation
CF3
CF3
+
+
CF3
3
4
NHNH2
O
N
N
1,4 addition
then condensation
SO2NH2
2
SO2NH2
Celecoxib 1
F3C
HN
OSO2Ph
N
N
O
cycloaddition
reaction
SO2NH2
5
Scheme 1. Precedented synthetic methods to access Celecoxib.
Regioselective
C5 - C-H arylation
CF3
In summary, we have developed a novel three linear step syn-
thesis of Celecoxib via regioselective N-arylation followed by a reg-
ioselective direct C–H arylation of a 1,3-disubstituted pyrazole.
N
N
Regioselective
N-arylation
N,N-Dibenzyl-4-iodobenzenesulfonamide (8)
4-Iodobenzenesulfonyl chloride (7) (3.34 g, 11 mmol) was dis-
solved in CH2Cl2 (20 mL). Et3N (2.31 mL, 16.6 mmol) was added
dropwise to the solution, followed by N-benzyl-1-phenylmethan-
amine (2.35 mL, 12.2 mmol) and the mixture was stirred at room
temperature under N2 for 16 h. The solvent was concentrated in
vacuo and the residue dissolved in EtOAc (20 mL). The organic
layer was washed with H2O (20 mL) and aqueous HCl (1.0 M,
20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to
generate an off-white solid. Yield = 4.71 g (92%).
SO2NH2
Scheme 2. Retrosynthetic plan to access Celecoxib.
exemplified further by Sames14 would give the best conversion
while ensuring regioselective arylation. To our delight, when the
intermediate 9 was treated with 4-bromotoluene under palladium
catalysis, C5 arylated product 10 was obtained after column chro-
matography in 66% yield as a single regioisomer,15 confirmed by
NMR experiments16 (NOESY and 1H NMR).
Deprotection of dibenzyl protected the sulfonamide 10 with
concentrated sulfuric acid and subsequent purification gave Cele-
coxib (1) in 69% yield and greater than 95% purity.
HPLC: Rt = 1.89 min, purity >95% by ELSD detection.
LRMS: m/z 464 [M + H]+.
1H NMR (400 MHz; DMSO-d6): d 4.28 (s, 4H), 7.05–7.07 (m, 4H),
7.18–7.20 (m, 6H), 7.61 (d, 2H, J = 8.59 Hz), 7.95 (d, 2H, J = 8.59 Hz).
O
O
O
O
S
S
NBn2
Cl
a)
I
I
7
8
CF3
CF3
CF3
CF3
b)
c)
d)
N
N
N
N
N
H
N
N
N
6
SO2NBn2
SO2NH2
SO2NBn2
9
10
1
Scheme 3. Reagent and conditions: (a) Bn2NH, Et3N, CH2Cl2, rt, 16 h, 92%; (b) CuI, N,N-dimethylcyclohexylamine, K3PO4, 1,4-dioxane, 115 °C, 50 h, 73%; (c) 1-bromo-4-
methylbenzene, Pd(OAc)2, PBuAd2, K2CO3, PivOH, DMA 140 °C, 50 h, 66%; (d) cH2SO4, rt, 2 h, 69%.

6002
S. M. Gaulier et al. / Tetrahedron Letters 52 (2011) 6000–6002
solution of saturated NaHCO3 (20 mL). The organic layer was col-
lected, dried over Na2SO4, filtered, and then concentrated in vacuo.
The residue was purified using chromatography on silica gel (via
ISCOÒ) eluting with EtOAc in heptane (0–30%). The solid obtained
was finally recrystallized from heptane to afford a white solid.
Yield = 0.160 g (69%).
N,N-Dibenzyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzen
esulfonamide (9)
3-(Trifluoromethyl)-1H-pyrazole (6) (1.23 g, 9.04 mmol), N,N-
dibenzyl-4-iodobenzenesulfonamide (8) (4.6 g, 9.93 mmol), and
K3PO4 (3.7 g, 17.4 mmol) were suspended in 1,4-dioxane (20 mL).
The mixture was heated to 80 °C then CuI (0.08 g, 4.2 mmol) and
N,N-dimethylcyclohexylamine (0.26 mL, 16.5 mmol) were added
and the mixture stirred at 115 °C for 50 h. The reaction was cooled
to room temperature and diluted with EtOAc (35 mL), washed with
a 1:1 solution of aqueous saturated NH3 and H2O (20 mL), then
washed with an aqueous solution of saturated NH4Cl (2 Â 30 mL).
The organic layer was collected, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was taken up in EtOAc
(25 mL) and then sonicated for 5 min. The solid obtained was col-
lected by filtration, and after drying under high vacuum for 2 h, a
very light-brown solid was obtained. Yield = 3.1 g (73%).
HPLC: Rt = 1.89 min, purity >95% by ELSD detection.
Spectroscopic details are consistent with those reported.2b
HPLC: Rt = 1.70 min, purity >95% by ELSD detection.
LRMS: m/z 382 [M + H]+.
1H NMR (400 MHz; CDCl3): d 2.38 (s, 3H), 4.99 (br s, 2H), 6.74 (s,
1H), 7.11 (d, 2H, J = 8.20 Hz), 7.18 (d, 2H, J = 8.01 Hz), 7.47 (d, 2H,
J = 8.59 Hz), 7.90 (d, 2H, J = 8.59 Hz).
13C NMR (100 MHz; CDCl3): 21.5, 106.6, 119.9, 125.7, 125.9,
127.7, 129.0, 130.0, 140.0, 141.6, 142.8, 145.5.
Anal. Calcd for C17H14F3N3O2S: C, 53.54; H, 3.70; N 11.02.
Found: C, 53.79; H, 3.65; N, 10.84.
Acknowledgments
LRMS: m/z 472 [M + H]+.
1H NMR (400 MHz; DMSO-d6): d 4.33 (s, 4H), 7.08–7.10 (m, 4H),
7.13 (d, 1H, J = 2.54 Hz), 7.18–7.23 (m, 6H), 8.03 (d, 2H, J = 8.98 Hz),
8.11 (d, 2H, J = 8.98 Hz), 8.90 (d, 1H, J = 2.54 Hz).
We would like to thank Dr. Dafydd Owen for his guidance and
helpful discussions.
13C NMR (100 MHz; CDCl3): 50.9, 107.2, 119.9, 128.0, 128.9,
129.3, 135.0, 135.7, 140.0, 142.3.
References and notes
1. (a) Battistone, M. J.; Sawitzke, A. D. Clin. Med. Insights: Ther. 2010, 2, 245–252;
(b) Schoenthal, A. H.; Chen, T. C.; Hofman, F. M.; Louie, S. G.; Petasis, N. A. Expert
Opin. Investig. Drugs 2008, 17, 197–208.
N,N-Dibenzyl-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-
2. (a) Ambati, V. R. R.; Garaga, S.; Mallela, S. P. S.; Meenakshisunderam, S. WO
2010095024 A2; Chem. Abstr. 2010, 153, 334033.; (b) Abdellatif, K. R. A.;
Chowdhury, M. A.; Dong, Y.; Velazquez, C.; Das, D.; Suresh, M. R.; Knaus, E. E.
Bioorg. Med. Chem. 2008, 16, 9694–9698; (c) Li, S. X.; Deng, X. D.; Jiang, F. L.;
Zhao, Y. J.; Xiao, W. S.; Kuang, X. Z.; Sun, X. M. Lett. Drug Design Discovery 2008,
5, 127–133; (d) Anumula, R. R.; Gilla, G.; Alla, S.; Akki, T. R.; Bojja, Y. US
20080234491 A1; Chem. Abstr. 2008, 149, 378735.
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Reddy, P. P. Org. Process Res. Dev. 2009, 13, 98–101.
4. Reddy, R.; Ramana, V.; Bell, S. C. WO 2003024958 A2; Chem. Abstr. 2003, 138,
271677.
pyrazol-1-yl]benzenesulfonamide (10)
N,N-Dibenzyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide (9) (0.527 g, 1.12 mmol), 1-bromo-4-methylbenzene
(0.38 g, 2.22 mmol), PBuAd2 (0.0301 g, 0.84 mmol), pivalic acid
(0.034 g, 0.333 mmol), and K2CO3 (0.465 g, 3.36 mmol) were dis-
solved in DMA (2 mL). The reaction mixture was degassed twice
with N2 before Pd(OAc)2 (0.0126 g, 0.56 mmol) was added and
the mixture stirred at 140 °C under N2 for 50 h. The reaction
was then diluted with EtOAc (15 mL) and washed with brine
(3 Â 15 mL). The organic phase was dried Na2SO4, filtered and
concentrated in vacuo. The residue was purified using chroma-
tography on silica gel (via ISCOÒ) eluting with TBME in heptane
5. Oh, L. M. Tetrahedron Lett. 2006, 47, 7943–7946.
6. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–238; (b)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–
9826.
7. (a) Rene, O.; Fagnou, K. Adv. Synth. Catal. 2010, 352, 2116–2120; (b) Mateos, C.;
Mendiola, J.; Carpintero, M.; Minguez, J. Org. Lett. 2010, 12, 4924–4927; (c) Do,
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2681–2685; (b) Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64,
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11. N1 arylation of 9 was confirmed via 13C NMR and NOESY experiments. In the
latter, an irradiation of the proton at 8.90 ppm (C5 position of the pyrazole)
gave rise to an NOE enhancement of the protons at 8.11 ppm (protons on aryl)
and at 7.13 ppm (C4 position of the pyrazole).
(0–10%) to provide the title compound as
Yield = 0.417 g (66%).
a white solid.
HPLC: Rt = 4.04 min, purity >95% by ELSD detection.
LRMS: m/z 562 [M + H]+.
1H NMR (400 MHz; CD3OD): 2.35 (s, 3H), 4.35 (s, 4H), 6.91 (s,
1H), 7.06–7.09 (m, 4H), 7.18–7.21 (m, 10H), 7.50 (d, 2H,
J = 8.98 Hz), 7.87 (d, 2H, J = 8.98 Hz).
13C NMR (100 MHz; CDCl3): 21.3, 51.2, 106.4, 119.2, 122.6,
123.0, 125.9, 127.7, 128.0, 128.8, 129.0, 131.5, 137.2, 141.0,
142.9, 145.0.
12. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496–16497.
13. Echavarren, A. M.; García-Cuadrado, D. A.; Braga, A. C.; Maseras, F. J. Am. Chem.
Soc. 2006, 128, 1066–1067.
Celecoxib (1)
14. Goikman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042–3048.
15. Product was contaminated with less than 5% of an identified di-arylated
impurity (C4 and C5 arylation of the starting pyrazole). No mono C4 arylated
product was obtained.
N,N-Dibenzyl-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-
pyrazol-1-yl]benzenesulfonamide (10) (0.34 g, 0.606 mmol) was
added portion wise to cH2SO4 (5 mL). The reaction was stirred at
room temperature for 2 h. The mixture was then added carefully
to cold H2O (30 mL) before extracting with TBME (2 Â 15 mL).
The organic layers were combined then washed with an aqueous
16. C4 arylation of 10 was confirmed via 1H NMR and NOESY experiments. In the
latter, an irradiation of the proton at 6.91 ppm (C4 position of the pyrazole)
gave rise to an NOE enhancement of the protons at 7.18 ppm (protons on the
tolyl group).