Ibuprofenamide: A convenient method of synthesis by catalytic hydration of 2-(4-isobutylphenyl)propionitrile in pure aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2011.06.026

An efficient and practical synthesis of the non-steroidal anti-inflammatory drug (NSAID) ibuprofenamide by catalytic hydration of 2-(4-isobutylphenyl) propionitrile is described. The readily accessible arene-ruthenium(II) complex [RuCl₂(η⁶-C₆Me₆){P(NMe ₂)₃}] is used as the catalyst, pure water as the solvent, and microwave irradiation as the heating source.

Full text of DOI:10.1016/j.tetlet.2011.06.026

Tetrahedron Letters 52 (2011) 4218–4220
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Tetrahedron Letters
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Ibuprofenamide: a convenient method of synthesis by catalytic hydration
of 2-(4-isobutylphenyl)propionitrile in pure aqueous medium
⇑
⇑
Rocío García-Álvarez, Javier Francos, Pascale Crochet , Victorio Cadierno
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica ‘Enrique Moles’ (Unidad Asociada al CSIC), Facultad de Química,
Universidad de Oviedo, Julián Clavería 8, E-33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practical synthesis of the non-steroidal anti-inflammatory drug (NSAID) ibuprofenamide
Received 3 May 2011
Revised 31 May 2011
Accepted 7 June 2011
Available online 13 June 2011
by catalytic hydration of 2-(4-isobutylphenyl)propionitrile is described. The readily accessible arene-
6
ruthenium(II) complex [RuCl
2
(
g
6
-C Me
6
){P(NMe
2 3
) }] is used as the catalyst, pure water as the solvent,
and microwave irradiation as the heating source.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Non-steroidal anti-inflammatory drugs
Ibuprofenamide
Nitrile hydration
Microwave irradiation
Ruthenium
Non-steroidal anti-inflammatory drugs (NSAIDs) are the first
choice of drugs in the treatment of pain, degenerative joint dis-
eases and rheumatic disorders. The clinical effects of NSAIDs are
based on the inhibition of the enzyme cyclooxygenase (COX),
considerable synthetic efforts have been made to mask the
carboxylic acid group of ibuprofen. In this sense, a large number
of amides able to in vivo deliver its parent acid 1 in a controlled
1
2
manner by hydrolysis of the –C(@O)NR R function have been
1
which catalyzes the formation of prostaglandins (PGs). Production
developed, some of them showing improved analgesic activity
4
,5
of PGs is induced at sites of inflammation, where they are involved
in the propagation of inflammation, pain, and fever. Inhibition of
PGs production alleviates these pathologic effects, but it also inter-
feres with the normal physiologic role of these molecules, that is,
cytoprotection of gastric mucosa, hemostasis, renal function, gesta-
and lower ulcerogenic effects. The simplest member of this fam-
ily, that is, ibuprofenamide (3), presents by itself a very good anti-
4
a,j
inflammatory activity,
and it has been used as an advanced
intermediate in the preparation of several N-substituted deriva-
4
e–g,k,m
tives with reduced ulcerogenic action.
Repertaxin, a non-
2
tion, and parturition. Consequently, long-term therapy with NSA-
competitive allosteric blocker of interleukin-8 (CXCL8/IL-8)
receptors (CXCR1/R2) belonging to the class of 2-phenylpropionyl
methanesulfonamides, is also produced starting from 3.6
IDs is frequently limited by their adverse effects, particularly those
3
caused by gastrointestinal bleeding, ulceration and perforation.
Ibuprofen, chemically 2-(4-isobutylphenyl)propionic acid (1), is
a well-known NSAID widely prescribed for the treatment of mus-
culoskeletal disorders, inflammation, fever, primary dysmenorrhea
and also in the management of mild pain.1 Similar to other pro-
totypical NSAIDs (aspirin, indomethacin, etc.), ibuprofen suffers
from the limitation of gastrointestinal toxicity caused by the pres-
ence of a carboxylic acid moiety in its structure.3
A common strategy in pharmaceutical research is the use of
well-established drugs as lead compounds to design new drug
candidates with improved therapeutic properties (the ‘prodrug
approach’). Accordingly, in order to minimize its negative effects,
The conventional method to prepare ibuprofenamide (3) in-
volves a two-step sequence consisting in the conversion of ibupro-
fen (1) to the acid chloride 2, by action of harmful thionyl chloride,
followed by treatment with aqueous or gaseous ammonia (Scheme
–3
4
a,e–g,j,k,m
1).
Herein, an alternative, efficient, and practical synthetic
approach to this valuable intermediate, via catalytic hydration of
2-(4-isobutylphenyl)propionitrile (4), is presented (Scheme 2).7
Hydration of nitriles is one of the most appealing and greener
routes presently available for the large-scale production of amides.
Traditionally, these hydration processes have been catalyzed by
strong acids and bases under harsh conditions, methods which
are not compatible with many sensitive functional groups and usu-
ally cause over-hydrolysis of the amides into the corresponding
⇑
Corresponding authors.
E-mail addresses: crochetpascale@uniovi.es (P. Crochet), vcm@uniovi.es (V.
8
carboxylic acids. It is now well-established that all these limita-
9
Cadierno).
tions can be circumvented by using enzymes and metal
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.026

R. García-Álvarez et al. / Tetrahedron Letters 52 (2011) 4218–4220
4219
Scheme 1. Classical synthesis of ibuprofenamide (3).
Figure 1. Structure of the ruthenium catalysts employed in this work.
Table 1
Ru-catalyzed hydration of 2-(4-isobutylphenyl)propionitrile (4) under thermal
a
conditions
Yield (%)b
TOF (h )c
À1
Entry
Catalyst
Time (h)
Scheme 2. Catalytic hydration of 2-(4-isobutylphenyl)propionitrile (4).
1
2
3
4
5
6
7
8
24
24
24
7
91 (80)
22
64
0.8
0.2
0.5
2.8
catalysts,10 several protocols for the selective formation of the
amides being presently available for practical applications. How-
ever, despite these recent advances, no efficient preparations of 3
by catalytic hydration of 4 have been reported to date.1
97 (87)
a
Reactions performed under N
in water). Substrate/Ru ratio:100/5.
2
atmosphere at 100 °C using 1 mmol of 4 (0.33 M
1,12
b
Yield of ibuprofenamide (3) determined by GC. Isolated yields after appropriate
In the course of our recent studies on metal-catalyzed nitrile
chromatographic work-up are given in brackets.
Turnover frequencies ((mol product/mol Ru)/time) were calculated at the
indicated time.
1
3
c
hydration reactions, we have found that the arene-ruthenium(II)
complex 5 and the bis(allyl)-ruthenium(IV) derivatives 6–7 are ex-
tremely efficient and selective catalysts for this transformation
(
Fig. 1), the presence of hydrosoluble P-donor ligands in these com-
Table 2
plexes allows us to run the catalytic reactions in pure aqueous
6-
Hydration of 2-(4-isobutylphenyl)propionitrile (4) catalyzed by complex [RuCl
C Me ){P(NMe ) }] (8) under MW irradiation
6 6 2 3
2
(g
medium at neutral pH.1
3a,b
With all these precedents in mind,
a
the ability of complexes 5–7 to promote the hydration of 2-(4-iso-
butylphenyl)propionitrile (4) into ibuprofenamide (3) under these
challenging reaction conditions has been explored as an alternative
method of synthesis of this relevant compound.
Yield (%)b
TOF (h )c
À1
Entry
Ru (mol %)
Time (h)
1
2
5
2.5
0.33
1
>99
>99 (91)
60.0
39.6
a
In a typical experiment, the corresponding ruthenium precursor
2
Reactions were performed under N atmosphere using 1 mmol of 4 (0.33 M in
Ò
water). A CEM Discover S-Class microwave was used (150 W, 150 °C).
5–7 (5 mol % of Ru) was added to a 0.33 M aqueous solution of 2-
b
Yield of ibuprofenamide (3) determined by GC. Isolated yield after appropriate
(
4-isobutylphenyl)propionitrile (4) and the mixture heated in an
chromatographic work-up is given in brackets.
oil-bath at 100 °C. The course of the reaction was monitored by
c
Turnover frequencies ((mol product/mol Ru)/time) were calculated at the
regular sampling and analysis by gas chromatography (GC). The re-
indicated time.
sults obtained are summarized in Table 1.
As expected from our previous works,1
3a,b
complexes 5–7 were
able to provide ibuprofenamide 3 as the unique reaction product
after 24 h of heating (ibuprofen was not detected by GC/MSD in
the crude reaction mixtures). However, only a good conversion
emerged as a promising new field of research within the ‘Green
1
7
Chemistry’ context. In this sense, as shown in Table 2, the
6
catalytic hydration of 4 by means of complex [RuCl
2 6 6
(g -C Me )
(
91% GC yield) could be attained with the mononuclear Ru(II) com-
{P(NMe }] (8) can be conveniently performed in pure water under
2 3
)
plex 5 (entry 1), the ruthenium(IV) species 6 and 7 being poorly
effective under the reaction conditions employed (22–64% GC
MW-irradiation, the working conditions employed (150 W/150 °C)
allowing to reduce drastically the reaction time. Thus, in the pres-
ence of 5 mol % of 8, quantitative formation of ibuprofenamide
was observed after only 20 min of irradiation (entry 1). More inter-
estingly, the use of MWs also allowed the reduction of the catalyst
loading without compromising the efficiency of the hydration pro-
cess. Thus, using only 2.5 mol % of 8, ibuprofenamide was generated
yield; entries 2–3). With the aim of finding a more efficient catalyst
6
for this relevant transformation other mononuclear [RuCl
Me )(PR
discovered that the readily accessible tris(dimethylamino)phosphine-
2
(g
-C
6
)] derivatives were checked,14 and to our delight we
6
3
6
15
based complex [RuCl
2 6 6 2 3
(g -C Me ){P(NMe ) }] (8) (5 mol %) is
able to generate the desired amide 3 in a remarkable 97% GC yield
in >99% GC yield after 1 h and could be isolated in analytically pure
16a
16b
after only 7 h of heating at 100 °C (entry 4 in Table 1).
Subse-
form with an excellent 91% yield (entry 2).
However, we must
quent purification by column chromatography on silica gel pro-
vided analytically pure ibuprofenamide in 87% isolated yield
note that all attempts made to recycle 8 by selective extraction of
ibuprofenamide from the aqueous phase failed.
In summary, an effective and practical synthesis of ibuprofena-
mide, a very valuable raw material for the design of novel NSAIDs,
has been developed by catalytic hydration of 2-(4-isobutyl-
1
13
1
(
copies of the H and C{ H} NMR and GC/MSD spectra of this
sample are given as Supplementary material).
The combined use of microwaves (MWs), as a nonclassical low-
energy-consuming heating source, and water, as an environmen-
tally friendly solvent, to perform organic reactions has recently
phenyl)propionitrile using the readily accessible arene-ruthe-
6
nium(II) complex [RuCl
2
(g
-C
6
Me
6
){P(NMe
2
)
3
}] (8). To the best

4
220
R. García-Álvarez et al. / Tetrahedron Letters 52 (2011) 4218–4220
of our knowledge this is the first efficient and selective protocol de-
Girolamo, M.; Martin, F.; Gentile, M.; Santoni, A.; Corda, D.; Poli, G.; Mantovani,
A.; Ghezzi, P.; Colotta, F. Proc. Natl. Acad. Sci. 2004, 101, 11791–11796.
Nitrile 4 is a commercially available compound (ABCR GmbH & Co. KG) that can
be generated by catalytic hydrocyanation of the corresponding vinylarene: (a)
Nugent, W. A.; McKinney, R. J. J. Org. Chem. 1985, 50, 5370–5372; (b)
Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.; Warren, T. H. J. Am. Chem.
Soc. 1994, 116, 9869–9882.
See, for example: (a) The Chemistry of Amides; Zabicky, J., Ed.; Wiley: New York,
1970; (b) Bailey, P. D.; Mills, T. J.; Pettecrew, R.; Price, R. A. In Comprehensive
Organic Functional Group Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.;
Elsevier: Oxford, 2005; Vol. 5, pp 201–294; (c) Methoden Org. Chem. (Houben
Weyl); Dopp, D., Dopp, H., Eds.; Thieme: Stuttgart, 1985; Vol. E5(2), pp 1024–
11,12
scribed in the literature for this transformation.
Moreover, the
7
.
.
process is truly sustainable since, in addition to its atom-economy,
it proceeds in a pure aqueous medium and is compatible with the
use of low-energy-consuming MW-irradiation as the heating
source. Further investigations into the application of complex
8
6
[
2
RuCl (g
-C
6
Me
6
){P(NMe
2
)
3
}] (8) to the catalytic hydration of
other challenging organonitriles are now in progress in our labora-
tories, and will be the subject of future contributions.
1031.
9
.
For recent reviews covering the use of enzymes in catalytic nitrile hydrations,
see: (a) Kobayashi, M.; Shimizu, S. Curr. Opin. Chem. Biol. 2000, 4, 95–102; (b)
Endo, I.; Nojori, M.; Tsujimura, M.; Nakasako, M.; Nagashima, S.; Yohda, M.;
Odaka, M. J. Inorg. Biochem. 2001, 83, 247–253; (c) Mylerová, V.; Martínková, L.
Curr. Org. Chem. 2003, 7, 1279–1295; (d) Kovacs, J. A. Chem. Rev. 2004, 104,
Acknowledgments
Financial support from the Spanish MICINN (Projects CTQ2006-
0
8485/BQU, CTQ2010-14796/BQU and CSD2007-00006) is grate-
825–848; (e) De Santis, G.; Di Cosimo, R. In Biocatalysis for the Pharmaceutical
fully acknowledged. J.F. thanks MEC of Spain and the European
Social Fund (FPU program) for the award of a Ph.D. grant.
Industry: Discovery, Development and Manufacturing; Tao, J., Lin, G.-Q., Liese, A.,
Eds.; Wiley-VCH: Weinheim, 2009; pp 153–181.
10. For reviews covering the field of metal-mediated and metal-catalyzed nitrile
hydrations, see: (a) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102,
Supplementary data
1
1
771–1802; (b) Kukushkin, V. Y.; Pombeiro, A. J. L. Inorg. Chim. Acta 2005, 358,
–21; (c) Ahmed, T. J.; Knapp, S. M. M.; Tyler, D. R. Coord. Chem. Rev. 2011, 255,
Supplementary data (Copies of the 31P{ H}, H and C{ H} NMR
1
1
13
1
949–974.
spectra of complex 8. Copies of the 1H and C{ H} NMR and GC/
13
1
11. The use of nitrile hydratases proved ineffective due to the preferential
formation of ibuprofen by hydrolysis of 3: (a) Beard, T.; Cohen, M. A.;
Parratt, J. S.; Turner, N. J.; Crosby, J.; Moilliet, J. Tetrahedron: Asymmetry 1993, 4,
MSD spectra of ibuprofenamide (3) isolated from entry 4 in Table
1
085–1104; (b) Effenberger, F.; Graef, B. W. J. Biotechnol. 1998, 60, 165–174; (c)
Fallon, R. D.; Stieglitz, B.; Turner, I. Appl. Microbiol. Biotechnol. 1997, 47, 156–
61; (d) Rzeznicka, K.; Schätzle, S.; Böttcher, D.; Klein, J.; Bornscheuer, U. T.
1. GC conditions employed and GC profiles of the catalytic reac-
tions) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.06.026.
1
Appl. Microbiol. Biotechnol. 2010, 85, 1417–1425.
1
2. Formation of ibuprofenamide by phase transfer catalyzed oxidation of 4 with
basic hydrogen peroxide has been described (up to 70% conversion with 90%
selectivity): Yadav, G. D.; Ceasar, J. L. Org. Process Res. Dev. 2008, 12, 740–747.
3. (a) Cadierno, V.; Francos, J.; Gimeno, J. Chem. Eur. J. 2008, 14, 6601–6605; (b)
Cadierno, V.; Díez, J.; Francos, J.; Gimeno, J. Chem. Eur. J. 2010, 16, 9808–9817;
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i
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4. Known compounds such as [RuCl
TPPMS, PTA, P(OMe) P(OPh)
conversion after 24 h at 100 °C).
2
(g
-C
6 6 3 3 3 3 3
Me )(PR )] (PR = PMe , PPh , P Pr ,
3
,
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3
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5. Preparation of complex [RuCl
2
(
g
6 6 2 3
Me ){P(NMe ) }] (8): A solution of dimer
6
[
{RuCl( ] (0.130 g, 0.194 mmol) in dichloromethane (20 mL)
l-Cl)(
g
-C
6
6
Me )}
2
was treated with P(NMe ) (0.352 mL, 1.94 mmol) at room temperature for 3 h.
2 3
The solution was then evaporated to dryness and the resulting oily residue
washed with a 1:2 mixture of diethyl ether/hexane (4 Â 10 mL), thus yielding
an orange solid which was vacuum-dried. Yield: 0.133 g, 71% (Found: C, 43.33;
1
9.
4
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1
H, 7.40; N, 8.60%. C18
H
36
N
3
Cl
3
, 162.1 MHz) d 114.9 (s) ppm. H NMR (CDCl , 400.5 MHz) d 2.68
13 1
2
PRu requires C, 43.46; H, 7.29; N, 8.45%). P{ H}
1
NMR (CDCl
3
d, 18H, 3
(
J
PH = 8.0 Hz, NMe), 1.96 (s, 18H, C
6
Me
6
) ppm. C{ H} NMR (CD
2 2
Cl ,
1
00.6 MHz) d 90.1 (s, C
6
Me ), 35.2 (br, NMe), 16.0 (s, C
6
6
6
Me ) ppm. Copies of the
spectra can be found in the Supplementary material.
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1
1
994, 29, 841–854; (e) Rajasekaran, A.; Sivakumar, P.; Jayakar, B. Indian J.
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[
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6
water (3 mL), and [RuCl
2 6 6 2 3
(g -C Me ){P(NMe ) }] (24.8 mg, 0.05 mmol;
5
mol % of Ru) were introduced into a sealed tube and the reaction mixture
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2
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by comparison of its 1H and C{ H} NMR spectroscopic data with those
13
1
reported in the literature and by their fragmentation in GC/MSD;
(
[
b) Catalytic hydration of 2-(4-isobutylphenyl)propionitrile (4) using complex
6
2 6 6 2 3
RuCl (g -C Me ){P(NMe ) }] (8) under MW-irradiation: Under nitrogen
atmosphere, a pressure-resistant septum-sealed glass microwave reactor vial
was charged with 2-(4-isobutylphenyl)propionitrile (0.187 g, 1 mmol), water
6
(
3 mL), [RuCl
2
(g
6
-C Me
6
){P(NMe
)
2 3
}] (12.4 mg, 0.025 mmol; 2.5 mol % of Ru)
and a magnetic stirring bar. The vial was then placed inside the cavity of a CEM
Ò
Discover S-Class microwave synthesizer and power was held at 150 W until
5
.
.
Esters are also prodrugs of ibuprofen under active investigation. See, for
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the desired temperature was reached (150 °C). Microwave power was
automatically regulated for the remainder of the experiment to maintain the
temperature (monitored by a built-in infrared sensor; Pmax = 25 psi). Work-up
as described above led to 0.187 g of analytically pure ibuprofenamide (91%
yield).
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