Palladium-mediated synthesis of novel nimesulide derivatives

Article abstract of DOI:10.1002/aoc.1666

Synthesis of a series of compounds structurally related to the anti-inflammatory agent nimesulide has been accomplished via Pd-catalyzed C-C bond forming reactions. Thus 4-iodo derivative, prepared from nimesulide, participated in Sonogashira (copper-free

Full text of DOI:10.1002/aoc.1666

Full Paper
Received: 12 February 2010
Revised: 4 April 2010
Accepted: 4 April 2010
Published online in Wiley Online Library: 28 June 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1666
Palladium-mediated synthesis of novel
nimesulide derivatives
Shylaprasad Durgadasa,b, Vijay kumar Chatarec, Khagga Mukkantia
and Sarbani Palc∗
Synthesis of a series of compounds structurally related to the anti-inflammatory agent nimesulide has been accomplished
via Pd-catalyzed C–C bond forming reactions. Thus 4-iodo derivative, prepared from nimesulide, participated in Sonogashira
(copper-free), Heck and Suzuki coupling reactions to afford the corresponding alkynyl, alkenyl and aryl substituted products.
c
Some of the compounds synthesized were tested for anti-inflammatory activities in vivo. Copyright ꢀ 2010 John Wiley & Sons,
Ltd.
Supporting information may be found in the online version of this article.
Keywords: nimesulide; anti-inflammatory; C–C bond; palladium; alkyne; alkene; boronic acid
Introduction
Experimental
General procedure for the preparation of N-(4-substituted-2-
Nimesulide [N-(4-nitro-2-phenoxyphenyl)methanesulfonamide,
1, Figure 1], a non-steroidal anti-inflammatory drug (NSAID), is a
moderately selective cyclooxygenase-2 (COX-2) inhibitor[1] which
is presently in patient use, although concerns have been raised
regarding its hepatotoxicity. Indeed because of the risk of hepa-
totoxicity, nimesulide has been withdrawn from market in many
countries and restricted by the European Medicines Agency. The
use of this drug has been reported to cause several types of liver
damage,[2] ranging from mild abnormal function to severe organ
injuries. These effects are usually reversible upon discontinuation
of the drug but occasionally can progress to fatal hepatic failure.[3]
The observed hepatotoxicity of 1 has often been linked to its
uncoupling effects on mitochondria and study has shown that
nimesulide exerts this effect via a protonopheretic mechanism
as well as oxidation of mitochondrial NADH and NADPH.[4] The
nitro group of nimesulide was thought to be responsible for
its protonophoretic and NAD(P)H oxidizing properties as chemi-
cal reduction of -NO2 to -NH2 completely suppressed the above
mitochondrial responses. It is therefore desirable to replace the
nitro group of 1 by an appropriate unsaturated group or sub-
stituent without affecting its anti-inflammatory, analgesic and
antipyretic properties. Accordingly, 4-cyano analog of nimesulide,
i.e. compound 2 (Fig. 1) was synthesized and identified as a potent
anti-inflammatory agent when tested in rats.[5]
phenoxyphenyl)methanesulfonamide (4–6)
ToasolutionofN-(4-iodo-2-phenoxyphenyl)methanesulfonamide
(1.0 mmol) in acetonitrile (10 ml) was added diisopropylethy-
lamine (1.5–3.0 mmol) and Pd(OAc)2 (0.10–0.19 mmol). The
mixture was stirred for 15 min at room temperature and the
appropriate coupling partner, e.g. a terminal alkyne or alkene or
arylboronicacid(1.0–8.0 mmol), wasadded. Themixturewasthen
stirred for 10–30 h at 75–80 ◦C. After the usual workup followed
by chromatographic purification the desired compound was ob-
tained in 53–82% yield (see below and Supporting Information).
Results and Discussion
The key starting material, i.e. N-(4-iodo-2-phenoxyphenyl)
methanesulfonamide (3), required for our synthesis was prepared
from nimesulide 1 via reduction of the nitro group[5] followed by
converting the resultant aryl amine to the iodo derivative under a
Sandmayer reaction condition (Scheme 2).
Having prepared the iodo compound 3 we then examined
its reactivity under the conditions of Sonogashira,[11] Heck-
Mizoroki[12] and Suzuki.[13] Although a wide variety of reaction
conditions have been reported individually for each of these C–C
bond forming methods we aimed to develop a common reaction
In our effort[6,7] to develop novel anti-inflammatory agents
derived from existing and well-known NSAIDs we have reported
synthesisandCOX-2inhibitorypropertiesofaseriesofdiarylethers
generated from nimesulide recently.[8] In further continuation
of our previous work we now wish to report a palladium-
mediated approach[9,10] to introduce unsaturated moieties at the
C-4 position of 1 in place of the nitro group (Scheme 1). To the
best of our knowledge preparation of nimesulide analogs via C–C
bond forming reactions under palladium catalysis has not been
reported earlier.
∗
Correspondenceto:Sarbani Pal,DepartmentofChemistry,MNRDegreeandPG
College,Kukatpally,Hyderabad500072,India.E-mail: sarbani277@yahoo.com
a
J N T University, Kukatpally, Hyderabad 500072, India
b
MSN Pharmachem Pvt. Ltd, Plot No. 212/A,B,C,D, APIICL, Phase-II, Pashamy-
laram, Patancheru (M), Medak District 502 307, Andhra Pradesh, India
c
Department ofChemistry, MNR DegreeandPG College, Kukatpally, Hyderabad
500 072, India
c
Appl. Organometal. Chem. 2010, 24, 680–684
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

Palladium-mediated synthesis of novel nimesulide derivatives
the presence of diisopropylethylamine, the use of other solvents
and bases was also examined. For example, the coupling reaction
provided slightly inferior yield of product 4a when triethylamine
was used as a base (entry 1 vs 2, Table 1) or DMF was used as
a solvent (entry 1 vs 3, Table 1) separately without changing the
other reaction parameters.
NHSO2CH3
O
Under the Heck reaction conditions compound 3 was coupled
with a variety of alkenes in the presence of Pd(OAc)2 and iPr2NEt
at 75–80 ◦C to afford the olefins (5a–e) in 53–66% yields (entries
6–10, Table 1). While acetonitrile was used a solvent in the present
reaction, the use of other solvents, e.g. DMF (entry 2, Table 2),
1,4-dioxane (entry 3, Table 2) and toluene (entry 4, Table 2), were
also examined for the coupling of methyl acrylate with 3. The
reaction proceeded well in these solvents except in toluene,
where inferior yield (∼40%) of product 5a was obtained. An
increase or decrease in reaction temperature from 75 to 80 ◦C also
decreased the product yield (entries 5 and 6 vs 1, Table 2). We have
chosenalkenespossessinganelectron-withdrawingesterorcyano
moiety in order to retain an electron-withdrawing effect similar to
nitro group at the C-4 position of nimesulide ring. Based on the
coupling constant of olefinic protons obtained from their 1H NMR
spectra (J = 15–16 Hz) all the olefins isolated were characterized
as E-isomers.
Finally, the compound 3 was coupled with 4-subtituted
arylboronic acids under Suzuki conditions to afford the aryl
substituted products 6a-c (entries 11–13, Table 1). Like earlier
reactions, once again Pd(OAc)2 was found to be an effective
catalyst in this case when the reaction was carried out at 75–80 ◦C
in acetonitrile. This catalyst was found to be equally effective
when DMF (entry 2, Table 3) or dioxane (entry 3, Table 3) was
used as a solvent. Although the reaction was carried out using
diisopropylethylamine as a base the use of inorganic bases such
as K3PO4 (entry 4, Table 3), Cs2CO3 (entry 5, Table 3) and K2CO3
(entry 6, Table 3) was also examined. However the isolated yield
Z
1. Z = NO2 (Nimesulide)
2. Z = CN
Figure 1. Nimesulide and its active analog.
conditionsforthesynthesisof ourtargetcompounds. Accordingly,
we conducted a preliminary study to establish the optimum
reaction condition in order to obtain the best yields of desired
products. The results of our palladium-catalyzed reaction leading
to various compounds (4–6) structurally related to nimesulide
are summarized in Table 1. The alkynyl derivatives 4a–c were
prepared in 75–82% yield via coupling of 3 with terminal
alkynes under copper-free Sonogashira conditions (entries 1–5,
Table 1). A copper-free method is advantageous as it precludes
the dimerization of terminal alkynes (the Glaser coupling) leading
to the formation of 1,3-diynes as side products and avoids the
possibility of copper contamination with the product.[14] Thus, in
a typical procedure to a solution of compound 3 (1.0 mmol) in
acetonitrile (10 ml) was added diisopropylethylamine (1.5 mmol)
and Pd(OAc)2 (0.10 mmol). The mixture was stirred for 15 min
at room temperature and the acetylenic compound (5.0 mmol)
was added. The mixture was then stirred according to the time
and temperature indicated in Table 1 and after the usual workup
followed by chromatographic purification the pure product was
isolated. Although the reaction was carried out in acetonitrile in
NHSO2CH3
NHSO2CH3
O
NHSO2CH3
R′
Heck
O
O
R
Sonogashira
4
5
I
3
R′
R
p-R′′C6H4B(OH)2 Suzuki
′=CO CH
R = C(CH3)2OH,
CH2(CH2)4CH3
C(CH3)3
R
2
3
CO2C2H5
CO2nBu
C6H5
NHSO2CH3
O
CN
6
R′′
R′′ = F, OCH3,CH2OH
Scheme 1. Preparation of nimesulide analogs via Pd-mediated C–C bond-forming reactions.
NHSO2CH3
O
NHSO2CH3
O
NHSO2CH3
O
NaNO2, HCl,
0-5 °C
H2, Pd/C
KI, 25-30 °C
3-4h, 54%
EtOAc, 5-6h
83%
I
NH2
NO2
1
3
Scheme 2. Preparation of N-(4-iodo-2-phenoxyphenyl)methanesulfonamide(3).
c
Appl. Organometal. Chem. 2010, 24, 680–684
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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S. Durgadas et al.
Table 1. Pd-mediated synthesis of alkynyl, alkenyland arylsubstituted compounds(4–6)structurally related to nimesulide from theiodo compound
3a
Alkynes/alkenes/arylboronic
acid
Reaction time (h)/temperature
(◦C)
Isolated
yield (%)
Entry
1
Products (4–6)
4a
10/75–80
75
OH
O
OH
H3CO2SHN
2
3
4
4a
4a
4b
10/75–80b
10/75–80c
10/75–80
69
71
79
OH
OH
CH2(CH2)4CH3
O
CH2(CH2)4CH3
H3CO2SHN
5
6
4c
5a
25/50–55
30/75–80
82
66
C(CH3)3
CO2CH3
O
H3CO2SHN
H3CO2SHN
C(CH3)3
O
O
CO2CH3
7
5b
25/75–80
61
CO2Et
H3CO2SHN
H3CO2SHN
CO2Et
8
9
5c
25/75–80
25/75–80
60
63
CO2nBu
O
O
CO2nBu
5d
C6H5
H3CO2SHN
H3CO2SHN
C6H5
10
11
5e
6a
25/75–80
53
55
CN
O
O
CN
10.0/75–80
F
B(OH)2
H3CO2SHN
H3CO2SHN
H3CO2SHN
F
12
13
6b
6c
10.0/75–80
10.0/75–80
67
61
H3CO
O
O
B(OH)2
OCH3
HOH2C
B(OH)2
CH2OH
a All the reactions were carried out using Pd(OAc)2, iPr2NEt in CH3CN.
b Et3N was used as a base in place of iPr2NEt.
c DMF was used as a solvent in place of CH3CN.
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2010, 24, 680–684

Palladium-mediated synthesis of novel nimesulide derivatives
anion in the presence of a base (Scheme 3) that eventually
participates in the subsequent steps. Thus reductive elimination
of Pd(0) from the alkynyl–aryl palladium(II)complex generated
in the case of Sonogashira reaction afforded the product 4.
A syn elimination of H–Pd(II)–I from the suitably configured
alkyl-palladium intermediate afforded the E-alkene 5 in case of
Heck reaction. Like Sonogashira coupling, a reductive elimination
of Pd(0) from di-aryl palladium(0) complex afforded the bi-aryl
coupled product 6 in the case of Suzuki coupling. In all these cases
the Pd(0) was regenerated to complete the catalytic cycle for each
coupling reaction.
We synthesized a range of alkynyl, alkenyl and aryl sub-
stituted novel compounds (4–6) structurally related to the
anti-inflammatory agent nimesulide. We then examined anti-
inflammatory activities of some of the compounds synthesized.
The anti-inflammatory activity was evaluated in a carrageenan-
induced rat model of inflammation[15] using indomethacin as a
reference compound. At a dose of 10 mg/kg (i.p.) compound 4a
showed 15, 20, 35 and 48% inhibition of edema after 1, 2, 3 and
4 h when indomethacin showed 24, 43, 66 and 93% inhibition at
10 mg/kg at the same time points. Similarly, compounds 4b and
4c showed 32 and 37% inhibition after 4 h at a dose of 10 mg/kg.
Table 2. Effect of reaction conditions on the Pd-mediated coupling
of methyl acrylate with iodo compound 3
Reaction time
(h)/temperature
Isolated yield
(%)
Entry
Solvent
Base
(◦C)
1
2
3
4
5
6
CH3CN
DMF
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
30/75–80
30/75–80
30/75–80
30/75–80
30/50–55
30/50–55
66
62
59
40
56
55
1,4-Dioxane
Toluene
CH3CN
DMF
Table 3. Effect of reaction conditions on the Pd-mediated coupling
of 4-flouropheylboronic acid with iodo compound 3
Reaction time
(h)/temperature
Isolated yield
(%)
Entry
Solvent
Base
(◦C)
1
2
3
4
5
6
CH3CN
DMF
iPr2NEt
iPr2NEt
iPr2NEt
K3PO4
10/75–80
30/75–80
30/75–80
30/75–80
30/50–55
30/50–55
55
54
55
48
51
49
1,4-Dioxane
CH3CN
CH3CN
CH3CN
Spectral data of selected compounds
Cs2CO3
K2CO3
Compound 5a
White solid, m.p. 154–155 ◦C; 1H NMR (400 MHz, DMSO-d6) δ 3.02
(s, 3H, CH3), 3.69 (s, 3H, CH3), 6.49 (d, J = 16.1 Hz, 1H, –CH ), 7.02
(d, J = 7.8 Hz, 2H, 2 × CH arom), 7.15 (t, J = 7.0 Hz, 1H, 1 × CH
arom), 7.29 (s, 1H, 1 × CH arom), 7.38–7.49 (m, 2H, 2 × CH arom),
7.51–7.53 (m, 2H, 2 × CH arom), 7.56 (d, J = 16.1 Hz, 1H, –CH ),
9.53 (bs, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ 38.2 (CH3),
51.3 (CH3), 117.7, 118.1, 119.2, 123.4, 123.9, 124.2, 129.8, 131.1,
131.5, 143.2, 148.2, 156.3, 166.4 (C O); IR (KBr, cm−1) 3251 (NH),
1724 (C O); MS (ES): m/z, 348.0 (M+, 100%). Elemental analysis
found: C, 58.52; H, 4.90; N, 4.20 C17H17NO5S requires C, 58.78;
H, 4.93; N, 4.03.
of product was found to be marginally inferior in these cases.
Similarly, increase or decrease in reaction temperature from
75–80 ◦C did not provide a better yield of product.
Mechanistically, all the coupling reactions (i.e. copper-free
Sonogashira, Heck or Suzuki) proceed via generation of a common
intermediate, e.g. aryl palladium complex X (Scheme 3), which
formed as a result of oxidative addition of Pd0 generated in situ
with the iodo compound 3. The organometallic intermediate
then undergoes (i) displacement of the iodo group by a terminal
alkyne in case of Sonogashira reaction, (ii) syn addition with
an alkene in case of Heck reaction or (iii) trans-metallation with
a boronic acid in case of Suzuki coupling. The copper-free
Sonogashira coupling proceeds via generation of an acetylide
Compound 5c
White solid; m.p. 138–139 ◦C; 1H NMR (400 MHz, DMSO-d6) δ 0.89
(t, J = 7.3 Hz, 3H, CH3), 1.32–1.38 (m, 2H, CH2), 1.56–1.61 (m,
2H, CH2), 3.0 (s, 3H, CH3), 4.11 (t, J = 6.5 Hz, 2H, CH2), 6.48 (d,
J = 15.6 Hz, 1H, –CH ), 7.02 (d, J = 7.8 Hz, 2H, 2 × CH arom),
7.10 (t, J = 7.3 Hz, 1H, 1 × CH arom), 7.30 (s, 1H, 1 × CH arom),
7.38–7.49 (m, 2H, 2 × CH arom), 7.51–7.58 (m, 3H, 2 × CH arom
and –CH ), 9.6 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ 13.5
(CH3), 18.6 (CH2), 30.2 (CH2), 40.6 (CH3), 63.6 (CH2), 118.1, 118.2,
119.2, 123.4, 123.9, 124.2, 129.8, 131.0, 131.6, 143.1, 148.2, 156.4,
166.0 (C O) IR (KBr, cm−1) 3248 (NH), 1730 (C O); MS (ES): m/z
390.0 (M+, 100%). Elemental analysis found: C, 61.75; H, 5.90; N,
3.53 C20H23NO5S requires C, 61.68, H, 5.95, N, 3.60.
R
NHSO2CH3
OC6H5
Base
R
4
Sonogashira
R
II
Pd
Pd(OAc)2
NHSO2CH3
OC6H5
Base
heat
NHSO2CH3
R′
OC6H5
Pd°
5
3
Heck
II
Pd
I
II
Pd
I
X
R′
Conclusions
NHSO2CH3
p-R′′C6H4B(OH)2
OC6H5
In conclusion, we have shown for the first time that the 4-iodo
analog of nimesulide participates in palladium-mediated C–C
bond forming reaction smoothly under Sonogashira (copper-
free), Heck or Suzuki[16–18] reaction conditions. This study yielded
a number of compounds of potential pharmacological interest.
Pd(OAc)2 and iPr2NEt were found to be a common and effective
6
Suzuki
II
p-R′′C6H4 Pd
Scheme 3. Reaction mechanism of Pd-mediated C–C bond forming
reactions leading to nimesulide derivatives.
c
Appl. Organometal. Chem. 2010, 24, 680–684
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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S. Durgadas et al.
catalyst and base, respectively, for these coupling reactions. Our
study provides easy access to the novel and diversity-based
compounds structurally related to nimesulide, synthesis of which
otherwise may be difficult or cumbersome via other conventional
methods.
[5] Y. Yoshikawa,Y. Ochi,K. Sekiuchi,H. Saito,K. Hatayama,Preparation
of sulfonanilide derivatives as antiinflammatory agents. Japan
patent application no. JP 02022260 A, 25 January 1990; Chem.
Abstr. 113, 77922.
[6] J. Jayaselli, J. M. S. Cheemala, R. D. P. Geetha, S. Pal, J. Braz. Chem.
Soc. 2008, 19, 509.
[7] S. Pal, P. Bindu, P. R. Venna, P. K. Dubey, Lett. Org. Chem. 2007, 4,
292.
[8] S. Pericherla, J. Mareddy, R. D. P. Geetha, P. V. Gollapudi, S. Pal,
Acknowledgments
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The author (S. Pal) thanks Mr M. N. Raju, the chairman of M. N. R.
Educational Trust for his constant encouragement.
[9] J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry: A Guide for
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Supporting information
Supporting information may be found in the online version of this
article.
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