Electrosynthesis of 2-arylpropionic acids from α-methylbenzyl chlorides and carbon dioxide by [Co(Salen)]

Article abstract of DOI:10.1081/SCC-200054748

The electrochemical synthesis of the 2-arylpropionic acid group of nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, indoprofen, biprofen, cicloprofen, and fenoprofen has been carried out in dimethylformamide (DMF) containing tetra-n-butylammonium perchlorate (nBu₄NClO ₄) by electrochemical carboxylation of α-methylbenzyl chlorides catalyzed by a schiff-base complex [Co(salen)] in an undivided cell equipped with a platinum cathode and magnesium anode under constant current density of 10 mA/cm² in good yields. Cyclic voltammetric studies have also been carried out to investigate the mechanism by which [Co(salen)] catalyzes the cathodic reaction of α-methylbenzyl chlorides in presence of CO ₂ by taking α-phenylethylchloride as the model compound. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054748

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Electrosynthesis of
2‐Arylpropionic Acids from
α‐Methylbenzyl Chlorides and
Carbon Dioxide by [Co(Salen)]
a
a
J. Damodar , S. Krishna Mohan , S. K. Khaja
a
a
Lateef & S. Jayarama Reddy
a
Electrochemical Research Laboratories,
Department of Chemistry, Sri Venkateswara
University, Tirupati, India
Published online: 16 Aug 2006.
To cite this article: J. Damodar , S. Krishna Mohan , S. K. Khaja Lateef & S. Jayarama
Reddy (2005): Electrosynthesis of 2‐Arylpropionic Acids from α‐Methylbenzyl Chlorides
and Carbon Dioxide by [Co(Salen)], Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:9, 1143-1150
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Synthetic Communications , 35: 1143–1150, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054748
Electrosynthesis of 2-Arylpropionic Acids
from a-Methylbenzyl Chlorides and
Carbon Dioxide by [Co(Salen)]
J. Damodar, S. Krishna Mohan, S. K. Khaja Lateef, and
S. Jayarama Reddy
Electrochemical Research Laboratories, Department of Chemistry,
Sri Venkateswara University, Tirupati, India
Abstract: The electrochemical synthesis of the 2-arylpropionic acid group of
nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, indoprofen,
biprofen, cicloprofen, and fenoprofen has been carried out in dimethylformamide
(
DMF) containing tetra-n-butylammonium perchlorate (nBu NClO ) by electrochemi-
4 4
cal carboxylation of a-methylbenzyl chlorides catalyzed by a schiff-base complex
Co(salen)] in an undivided cell equipped with a platinum cathode and magnesium
[
2
anode under constant current density of 10 mA/cm in good yields. Cyclic voltam-
metric studies have also been carried out to investigate the mechanism by which
[
Co(salen)] catalyzes the cathodic reaction of a-methylbenzyl chlorides in presence
of CO by taking a-phenylethylchloride as the model compound.
2
Keywords: Benzyl chloride, carbon dioxide, carboxylic acid, cobalt complex, cyclic
voltammetry
INTRODUCTION
Electroreductive carboxylation of organic halides with CO is an interesting
2
[
1–6]
method for the synthesis of carboxylic acids.
Catalytic systems based
Received in India December 13, 2004
Address correspondence to S. Jayarama Reddy, Electrochemical Research
Laboratories, Department of Chemistry, Sri Venkateswara University, Tirupati,
India. Tel: +91-877-2249962; Fax: þ91-877-2248499/2249111; E-mail:
profjreddy_s@yahoo.com

1144
J. Damodar et al.
on transition-metal complexes have been proposed to improve the yield of
electrocarboxylations. The electrochemistry of the cobalt complexes has
been extensively studied and it has been shown that the cobalt(I) complexes
have strong nucleophilic properties with a stable cobalt–carbon bond
commonly resulting from the reactions with electrophiles and it is well
known that nucleophilic cobalt(I) complexes readily react with organic
[7]
halides to give the corresponding organometallic complexes. Electrochemi-
cal reaction of these complexes has been investigated by several groups and
the electrochemical carboxylation of organic halides including benzylic and
allylic chlorides has been shown to be catalyzed by [Co(salen)]
0
[8–11]
(
salen ¼ N,N -bis[salicylidenethane-1,2-diamine).
The use of low-
valent-metal complexes as catalysts makes the reduction of organic halide
easier. The electrochemical studies have shown that Co(salen) in its reduced
form, cobalt(I), permits the catalytic reduction of organic halides.
[
12–14]
Fauvarque et al.
reported the syntheses of the 2-arylpropionic acid
class of nonsteroidal anti-inflammatory agents through electrocarboxylation
of a-methylbenzyl chlorides by using nickel complexes. As part of our con-
tinuing studies on the electrochemical carboxylation of k-methylbenzyl
[
15]
chlorides using transition-metal catalysts,
to improve the yield of electro-
carboxylations, we carried out the electrocarboxylation of k-methylbenzyl
chlorides using the schiff base Co(salen) catalyst. In this communication we
describe the synthesis and mechanism of electrochemical carboxylation of
k-methylbenzyl halides in DMF catalyzed by Co(salen) in a CO saturated
2
solution in an undivided cell equipped with a platinum cathode and a
2
magnesium anode under a constant current density of 10 mA/cm .
EXPERIMENTAL
Electrolyses were carried out using Potentiostat (model PS 605). Melting
points were determined on Mel-Temp apparatus and are uncorrected.
1
H NMR was recorded on a Varian EM-360. IR spectra were recorded on a
Perkin-Elmer 1600. Cyclic voltammetric measurements were carried out
with a Metrohm unit 757VA Computrace at hanging mercury drop
electrode (HMDE) of area 0.15 mm and Ag/AgCl as the reference
electrode. Solvent DMF was distilled over CaH . nBu NClO (Fluka) was
2
4
4
recrystallized from ethanol. The model compound a-phenylethyl
[18]
[
16]
[17]
[17]
chloride
biprofen,
and the precursors of ibuprofen,
[20]
naproxen,
[17]
indoprofen,
as a-methylbenzyl
[17,19]
cicloprofen,
and fenoprofen

Electrosynthesis of 2-Arylpropionic Acids
1145
chlorides were prepared according to the literature. The complex [Co(salen)]
[
was prepared as described in the literature.
21]
Electrochemical Carboxylation
Electrolysis was carried out in an undivided cell equipped with a Pt cathode and
a Mg anode. The cell was first charged with 50 ml of solvent DMF containing
nBu NClO (4 mmol) as the supporting electrolyte. Then, the starting halide
4
4
1
-chloro-1-(4-isobutylphenyl)ethane (a precursor of ibuprofen) (20 mmol)
was added to the cell, followed by a catalyst [Co(salen)] (1 mmol). Before
electrolysis, the O in the system was removed by passing N gas through
this solution. After that, the solution was saturated by bubbling CO for 1 h.
2
2
2
In this saturated state, the system was electrolyzed at a constant current
2
2
21
density of 10 mA cm until 2 F mol had been passed through the cell at
8C. Usual workup of the electrolyzed solution afforded 2-(4-isobutylphenyl)-
propionic acid (ibuprofen) in 83% isolated yield.
-(4-Isobutylphenyl)propionic acid (ibuprofen): mp 75–768C (lit.
5
[
22]
2
mp
2
1 1
7
0–728C); IR (neat): n ¼ 1700 cm ; H NMR (CDCl ): d ¼ 1.1 (d, 6H,
3
J ¼ 4.8), 1.5 (d, 3H), 1.75–1.95 (dd, 1H), 2.45 (d, 2H), 3.68 (q, 1H,
J ¼ 4.8), 7.0–7.3 (m, 4H), 11.56 (s, 1H).
2
23]
-(6-Methoxy-2-naphthyl)propionic acid (naproxen): mp 156–1578C
21 1
[
(
lit.
mp 160–1618C); IR (neat): n ¼ 1720 cm
; H NMR (CDCl3):
d ¼ 1.6 (d, 3H, J ¼ 4.7), 3.86 (q, 1H, J ¼ 4.7), 3.92 (s, 3H), 7.02–7.7
(
m, 6H), 11.57 (s, 1H).
2
-[4-(1-Oxo-2-isoindolinyl)phenyl]propionic acid (indoprofen): mp
21 1
[18]
2
12–2138C (lit.
mp 213–2148C); IR (neat): n ¼ 1690 cm ; H NMR
(
CDCl ): d ¼ 1.37 (d, 3H, J ¼ 7.0), 3.68 (q, 1H, J ¼ 7.0), 5.0 (s, 2H), 7.2–
3
8
.0 (m, 8H), 11.65 (s, 1H).
2
[
24]
-(2-Biphenyl)propionic acid (biprofen): mp 145–1468C (lit.
mp
2
1
1
1
47–1488C); IR (neat): n ¼ 1700 cm ;
d, 3H), 3.65 (q, 1H), 6.97–7.44 (m, 9H), 11.52 (s, 1H).
H NMR (CDCl ): d ¼ 1.46
3
(
[25]
2
-(2-Fluorene)propionic acid (cicloprofen): mp 184–1858C (lit.
mp
2
1
1
1
81–1838C); IR (neat): n ¼ 1710 cm ;
d, 3H), 3.2 (s, 2H), 3.74 (q, 1H), 7.14–7.63 (m, 7H), 11.54 (s, 1H).
H NMR (CDCl ): d ¼ 1.43
3
(
[26]
2
-(3-Phenoxyphenyl)propionic acid (fenoprofen): bp 168–1698C (lit.
bp 168–1718C); IR (neat): n ¼ 1720 cm ; H NMR (CDCl ): d ¼ 1.50
2
1
1
3
(
d, 3H), 3.71 (q, 1H), 6.92–7.50 (m, 9H), 11.54 (s, 1H).
RESULTS AND DISCUSSION
The electrochemical carboxylation of precursors of ibuprofen, naproxen, indo-
profen, biprofen, cicloprofen, and fenoprofen were examined under various

1146
J. Damodar et al.
electrolytic conditions. The proper choice of cathode material was found to
have a large effect on the electrocarboxylation on the a-methylbenzyl
chlorides at higher concentrations. Although the acids were obtained in very
low yields when an Ni, Cu, or C cathode was used, the product started to
deposit at the cathode except for Pt. For example, ibuprofen was obtained
in lower yields with Ni (75%), Cu (67%), and C (60%) compared with Pt
2
(83%) as cathodes. A current density of 10 mA/cm was accessible and con-
sumption of 2 F/mol of halide was required for efficient carboxylation. For
efficient electrolysis, DMF is considered to be a good solvent because of the
a
Table 1. Electrochemical synthesis of 2-arylpropionic acids
Yield
b
(%)
ArCH(CH
3
)Cl
ArCH(CH
3
)COOH
8
3
8
0
8
8
6
5
8
7
4
8
a
ArCH(CH
3
)Cl ¼ 20 mmol, Co(salen) ¼ 1 mmol, nBu
4
NClO
electricity ¼ 2 F mol
4
21
¼ 4 mmol, DMF ¼
2
2
2
,
5
0 ml, current density ¼ 10 mA cm
,
PCO
¼ 1 atm.
cathode ¼ Pt, anode ¼ Mg.
b
Isolated yields.

Electrosynthesis of 2-Arylpropionic Acids
1147
Scheme 1.
higher solubility of the acid in this solvent. Less concentrated solutions
allowed the electrolysis to proceed with a good yield without deposition at
the cathode. The presence of the catalyst influenced the chemical yield.
Table 1 gives the results of electrocarboxylation of a-methylbenzyl
chlorides catalyzed by Co(salen) at the Pt cathode and Mg anode. The
increase in the yield of 2-arylpropionic acids in presence of Co(salen) when
[
15]
compared with using PdCl (PPh )
2
may be due to the strong nucleophilic
3 2
properties of Co(I) complexes.
This electroreaction of arylalkylhalide with CO catalyzed by [CoL] has
2
a different mechanism and the probable reaction pathways of the present
electrochemical carboxylation are shown in Scheme 1. In electrolysis, the
2
central cobalt of [CoL] was electroreduced from [Co(II)L] to [Co(I)L] ,
Figure 1. Cyclic voltammograms of (a) 1 mmol [Co(salen)], (b) as (a) þ10 mmol
PhCH(CH )Cl, (c) as (b) in presence of CO
HMDE at 0.2 V/s.
3
2
4 4
in DMF þ 10 mmol nBu NClO at

1148
J. Damodar et al.
2
which is the actual catalyst of the reaction. The formed [Co(I)L] anion
possesses strong nucleophilicity. The first step of the electrocatalytic
reaction of arylalkylhalide (RX) is the oxidative addition of electrogenerated
2
[Co(I)L] to form organometallic complex [RCo(III)L]. One electron
reduction of organometallic complex [RCo(III)L] gives the unstable species
2 2
RCo(II)L] . The decomposition of [RCo(II)L] in the presence of CO2
[
was the key step in the reaction. This step may consist of a direct attack of
2
CO on [RCo(II)L] followed by bond breaking to give carboxylate and
2
[Co(II)L].
Cyclic Voltammetry
The cyclic voltammetry of [CoL] in DMF containing nBu NClO as the sup-
4
4
porting electrolyte shows a reversible peak at E ¼ 21.28 V vs Ag, or AgCl at
p
0
.2 V/s. Addition of PhCH(CH )Cl to this strongly modifies the voltammetric
3
pattern of the complex. The cathodic peak shifted to less negative potentials
and its anodic peak completely disappears. This indicates that the chemical
2
reaction occurs between [Co(I)L] and PhCH(CH )Cl. When CO is passed
3
2
to the solution, the reduction peak of the organocobalt complex is substantially
enhanced. Figure 1 shows cyclic voltammogram of [CoL] in the presence of
PhCH(CH )Cl under CO .
3
2
CONCLUSIONS
It can be observed that, when carried out in the presence of CO , the electro-
2
chemical reduction of a-methylbenzyl chlorides catalyzed by [CoL] leads to
the corresponding 2-arylpropionic acids in good yields.
ACKNOWLEDGMENTS
J.D. is thankful to Council of Scientific and Industrial Reseacrh, New Delhi,
India, for providing financial assistance in the form of a Senior Research
Fellowship.
REFERENCES
1. Silvestri, G.; Gambino, S.; Filardo, G.; Greco, G.; Gulotta, A. Electrochemical
carboxylation of benzyl chloride. Tetrahedron Lett. 1984, 25, 4307.
2. Sock, O.; Troupel, M.; Perichon, L. Electrosynthesis of carboxylic acids from
organic halides and carbon dioxide. Tetrahedron Lett. 1985, 26, 1509.

Electrosynthesis of 2-Arylpropionic Acids
1149
3
4
. Pouliquem, J.; Heintz, M.; Sock, O.; Troupel, M. Carboxylic acids from halides
and carbon dioxide. J. Chem. Edu. 1986, 63, 1013.
. Chaussard, J.; Folest, J. C.; Nedelec, J. Y.; Perichon, J.; Sibille, S.; Troupel, M. Use
of sacrificial anodes in electrochemical functionlization of organic halides.
Synthesis 1990, 369.
5. Silvestri, G.; Gambino, S.; Filardo, G.; Gulotta, A.. Sacrificial anodes in the
elctrocarboxylation of organic halides. Angew. Chem., Int. Ed. Engl. 1984, 23, 979.
6. Silvestri, G.; Gambino, G.; Filardo, G. Use of sacrificial anodes in synthetic electro-
chemistry: Processes involving carbon dioxide. Acta Chem. Scand. 1991, 45, 987.
7. Maiya, G. B.; Han, B. C.; Kadish, K. M. Electrochemical studies of cobalt–carbon
bond formation: A kinetic investigation of the reaction between (tetraphenylpro-
phinato)cobalt(I) and alkyl halides. Langmuir 1989, 5, 645.
8
. Isse, A. A.; Gennaro, A.; Vianello, E. The electrochemical reduction mechanism of
0
[N, N - 1, 2-phenylene bis(salicylideneiminato)]cobalt(II). J. Chem. Soc. Dalton
Trans. 1993, 2091.
. Fry, A. J.; Sirisoma, U. N. Electrocatalytic reduction of benzyl chloride by cobalt
9
(
0. Chung, W. H.; Guo, P.; Wong, C. P.; Lau, C. P. Electrocarboxylation of aryl
I)(salen): A mechanistic investigation. J. Org. Chem. 1993, 58, 4919.
1
1
1
1
1
0
0
methyl chlorides catalyzed by cobalt 6,6 -bis(2-hydroxyphenyl)-2,2 -bipyridine.
J. Electroanal. Chem. 2000, 32, 486.
1. Isse, A. A.; Gennaro, A.; Vianello, E. Electrochemical carboxylation of aryl
0
methyl chlorides catalyzed by [Co(salen)] [H2 salen ¼ N,N -bis(salicylidene
ethane-1,2-diamine]. J. Chem. Soc. Dalton Trans. 1996, 1613.
2. Fauvarque, J. F.; Jutand, A.; Francois, M. Nickel catalysed electrosynthesis of anti-
inflammatory agents: Part I: Synthesis of 2-arylpropionic acids, under galvanostas-
tic conditions. J. Appl. Electrochem. 1988, 18, 109.
3. Fauvarque, J. F.; Jutand, A.; Francois, M.; Petit, M. A. Nickel-catalyzed electro-
synthesis of anti-inflammatry agents: Part II: Monitoring of the electrolyses by
HPLC analysis: Role of the catalyst. J. Appl. Electrochem. 1988, 18, 116.
4. Fauvarque, J. F.; De Zelicourt, Y.; Amatore, C.; Jutand, A. Nickel-catalyzed elec-
trosynthesis of anti-inflammatry agents: Part III: A new electrolyzer for organic
solvents: Oxidation of metal power as an alternative sacrificial anodes. J. Appl.
Electrochem. 1990, 20, 338.
1
5. Damodar, J.; Krishna Mohan, S.; Jayarama Reddy, S. Synthesis of 2-arylpropionic
2 3 2
acids by electrocarboxylaiton of benzylchlorides catalysed by PdCl (PPh ) .
Electrochem. Commun. 2001, 3, 762.
1
6. Moye, C. J. The purity of (alpha)-chloroethylbenzyne. Aust. J. Chem. 1967, 20, 779.
7. Hayashi, T.; Konishi, M.; Fukushima, M.; Kanemira, K.; Hioki, T.; Kumada, M.
Chiral(beta-aminoalkyl)phosphines. Highly efficient phosphine ligands for
catalytic asymmetric grignard cross-coupling. J. Org. Chem. 1983, 48, 2195.
8. Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Haga, S.; Shirayama, K.
Studies on the synthesis of analgestic—part 50(1). Synthesis of optically active
1
1
2-[4-(1-exo-2-isoindoleinyl)phenyl]propanoic acid. [Studies on the synthesis of
heterocyclic compounds, Part 742(2)]. J. Heterocyclic Chem. 1978, 15, 369.
1
9. Ferris, C. V.; Turner, E. E. Studies in ring formation: Part - III: The condentation of
0
aromatic amines with a- and b-diketones and with 4 : 4 -diacetylidiphenyl.
J. Chem. Soc. 1920, 117, 1140.
2
0. Ray, F. E.; Rieveschi, G., Jr. 2-Acetylfluorene (ketone, 2-fluorenyl methyl). Org.
Synthesis 1955, 3, 23.

1150
J. Damodar et al.
2
2
2
1. Floriani, C.; Calderazzo, F. Oxygen adducts of schiff’s base complexes of cobalt
prepared in solution. J. Chem. Soc. A 1969, 946.
2. Faigl, F.; Schlosser, M. A one-pot synthesis of ibuprofene involving three consecu-
tive steps of superbase metalation. Tetrahedron Lett. 1991, 32, 3369.
3. Shishido, K.; Yamashita, A.; Hiroya, K.; Fukumoto, K. Synthesis of 2,6-
disubstituted dihydronaphthalenes and naphthalenes by electrocyclic reaction of
o-quinodimethane. A synthesis of (+)naproxen. J. Chem. Soc. Perkin Trans.
1990, 1, 469.
2
2
2
4. Biaocchi, L.; Bonanomi, M.; Giannangeli, M.; Picconi, G. Aromatization of
aliphatic compounds IV: On the aromatization of some dihydrobenzofuranones.
Synthesis 1979, 434.
5. Stiller, E. T.; Diassi, P. A.; Gerschutz, D.; Meikle, D.; Moetz, J.; Principe, P. A.;
Levine, S. D. Synthesis and antinflammatory activities of a-methyl fluorine-2-
acetic acid and related compounds. J. Med. Chem. 1972, 15, 1029.
6. Rubin, A.; Knadler, M. P.; Ho, P. P.K.; Bechtol, L. D.; Wolen, R. L. Stereoselec-
tive inversion of (R)-fenoprofen to (S)-fenoprofen in humans. J. Pharm. Sci. 1985,
74, 82.