Facile synthesis of α-hydroxy-α-methyl carboxylic acids by electrochemical carboxylation of methyl aryl ketones

Article abstract of DOI:10.1055/s-2002-20042

Electrochemical carboxylation of methyl aryl ketones in the presence of atmospheric pressure of carbon dioxide using platinum cathode and dissolved magnesium anode at constant current density of 10 mA/cm² gave the corresponding α-hydroxy-α-meth

Full text of DOI:10.1055/s-2002-20042

PAPER
399
Facile Synthesis of -Hydroxy- -Methyl Carboxylic Acids by Electrochemical
Carboxylation of Methyl Aryl Ketones
E
lectroche
a
mical
C
arb
n
oxylationof
m
M
ethyl
A
ryl
K
eton
a
es nchi Damodar,a Srinivasulu Reddy Krishna Mohan,b Srinivasulu Reddy Jayarama Reddy*a
a
Electrochemical Research Laboratories, Department of Chemistry, Sri Venkateswara University, Tirupati 517502, India
Fax 91(875)448499; E-mail: jreddy_s@yahoo.com
b
Department de Chimie Organique, Universite de Geneve, Quai Ernest-Ansermet 30, 1211 Geneve 4, Switzerland
Received 11 October 2001; revised 9 December 2001
Traditionally -hydroxy acids can be prepared via the cor-
responding cyanohydrins using hydrogen cyanide18 and
Grignard reagent.19 However, the need to use highly toxic
cyanides makes this process less attractive and somewhat
Abstract: Electrochemical carboxylation of methyl aryl ketones in
the presence of atmospheric pressure of carbon dioxide using plati-
num cathode and dissolved magnesium anode at constant current
density of 10 mA/cm2 gave the corresponding -hydroxy- -methyl
carboxylic acids in 79–84% isolated yields. The precursor of ciclo- troublesome from the point of view of industry, particu-
profen, -hydroxy- -methylfluorene-2-acetic acid (1a) and bipro-
fen, -hydroxy- -methybiphenyl-4-acetic acid (2a) were readily
larly for the production of pharmaceuticals, which are for
human consumption. Alternatively, the -hydroxy acids
obtained in good yield by a similar electrochemical carboxylation of
can be prepared via electrocarboxylation of the corre-
2-acetylfluorene (1) and 4-acetylbiphenyl (2). Cyclic voltammetric
sponding methyl aryl ketones with a mercury cathode in a
studies showed that the reaction is reversible indicating the prefer-
divided cell.6 While the reported yields are good, the use
ential generation of stable anion radicals from methyl aryl ketones
of highly toxic mercury was environmentally unaccept-
able and the use of a divided cell substantially increased
the cost of production and the system was impractical for
its development into commercially useful processes. In
order to develop a convenient and commercially useful
synthetic method of drugs and its precursors, it is desir-
able to evolve a high yield system with an undivided cell,
performing electrochemical carboxylations. In this paper,
we report the yields obtained for an effective synthesis of
-hydroxy- -methyl carboxylic acids via the electro-
chemical carboxylation of methyl aryl ketones using an
undivided cell with a sacrificial magnesium anode at con-
stant current density using different supporting electro-
lytes by passing carbon dioxide into dimethylformamide.
The use of sacrificial metal anode eliminates the problems
of the cathodic reactions.20–23 Using Mg as reactive metal
anode, the metal ions arising from the anodic reaction
form stable complexes with carboxylate ions which can be
isolated on completion of the electrolysis. The salts of the
carboxylate ion could be easily removed during the work-
up since the synthesis is carried out in an undivided cell.
and that further addition of carbon dioxide does not take place in
these electrochemical carboxylations.
Key words: carbon dioxide, electrochemical carboxylation -hy-
droxy- -methylcarboxylic acids, methyl aryl ketones, sacrificial
anode, cyclic voltammetry
Electrochemical carboxylation is one of the most useful
methods for the fixation of carbon dioxide into organic
substrates. Even in the atmospheric pressure of carbon di-
oxide, electrochemical carboxylation takes place effi-
ciently by the use of a reactive metal anode, such as
magnesium, aluminum or zinc.1,2 In recent years there has
been increased interest in the development of economical
process for the production of -hydroxy acids, which can
be carboxylated to the corresponding methyl ary ke-
tones.3–7 Tokuda et al. has already reported an efficient
electrochemical carboxylation of various organic sub-
strates using a magnesium anode.8–13 Aryl-2-propionic ac-
ids including cicloprofen and biprofen constitute an
important class of non-steroidal anti-inflammatory
drugs14 which can be synthesised from -hydroxy acids.
As -hydroxy- -methylfluorene-2-acetic acid (1a) and -
hydroxy- -methylbiphenyl-4-acetic acid (2a) are valu-
able precursors of cicloprofen and biprofen respectively,
syntheses of these precursors are beneficial for medicinal
chemistry. The earliest studies of electrocarboxylation of
methyl aryl ketones reported a low yield of carboxylated
products15,16 and later were improved due to the fact that
methyl aryl ketones could be electrochemically carboxy-
lated in good yields in an undivided cell using an oxalate
electrode.17
Electrochemical carboxylation of methyl aryl ketones are
carried out at 5 °C at a constant current of 10 mA/cm2 until
2 F/mol electricity has been passed in DMF containing
tetrabutylammonium bromide in the presence of atmos-
pheric pressure of carbon dioxide in an undivided cell
equipped with a platinum cathode and dissolved sacrifi-
cial magnesium anode. Electrochemical carboxylation of
2-acetlylfluorene (1) and 4-acetylbiphenyl (2) readily
takes place to give -hydroxy- -methylfluorene-4-acetic
acid (1a) and -hydroxy- -methylbiphenyl-4-acetic acid
(2a) as sole carboxylation products, respectively, in 79–
84% yields (Scheme 1). For the convenience of product
analysis, the carboxylated product is then analysed by 1H
NMR and IR spectra. This electrochemical carboxylation
is examined under a variety of electrolysed conditions.
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0399,0402,ftx,en;Z11301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

400
J. Damodar et al.
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Scheme 1
Tetrabutylammonium bromide, tetraethylammonium bro- effective. Another metal halide supporting electrolyte
mide, sodium bromide and potassium bromide were used tried was sodium bromide. In that case, an insoluble ma-
as supporting electrolytes and DMF and acetonitrile as terial was formed on the cathode; probably sodium salts,
solvents. In our study of the electrochemical carboxyla- which caused early termination of electrolysis. This metal
tion of 1 and 2, we found that the selectivity for the desired halide including potassium bromide was much inferior
products 1a and 2a were quite sensitive to the reaction and gave lower yields of the carboxylation product. A
media and the reaction conditions. Among the common comparison of the effect of these electrolytes and solvents
solvents, DMF is found to be most effective for the reac- under similar conditions is summarised in the Table.
tion, probably due to the higher solubility of the carboxy-
In the present electrochemical carboxylations using plati-
lation product in this solvent. In acetonitrile (a commonly
num cathode and magnesium anode, the -hydroxy- -me-
used electrochemical solvent and a good alternative for
thyl acetic acids 1a and 2a are preferentially produced in
good yields. The results show that the sacrificial magne-
the reaction) and less polar solvents, such as N-methylpyr-
rolidinone (NMP) the carboxylation product precipitated
sium anode plays an important role in the efficient electro-
on the electrode during the reaction. The salt that precipi-
chemical carboxylation. In electrolysis, a one-electron
tated from the acetonitrile solution during the reaction is
reduction of methyl aryl ketone gives the radical anion.
moderately slow to filter due to the formation of sludge
This radical anion attacks carbon dioxide followed by the
and observed byproduct formation like pinacol type
addition of second electron to give the carboxylate anion
dimer. This is because the starting methyl aryl ketone
at cathode. At an anode, on the other hand, dissolution of
takes one electron from the cathode to become an anion
magnesium takes place to give magnesium ion and this
radical in the presence of protic solvents; the anion radical
magnesium ion readily captures carboxylate ion to form
get protonated to form neutral hydroxyl radical which
dimerises to the pinacol type byproduct. This decreases
the product yield. For this reason it is important to use an-
hydrous, non-protic solvents for the electrochemical car-
boxylation of methyl aryl ketones. When higher
concentration of carbon dioxide is used, the radical inter-
mediate is more rapidly trapped and converted to the de-
sired product. The higher concentration of carbon dioxide
was achieved by using lower reaction temperature (at 0
°C) and higher pressure of carbon dioxide. Lower concen-
tration of the substrate also gave the better selectivity of
the desired product. This is consistent with alleviation of
the dimerisation problem. Lower concentration of starting
material resulted in relatively less formation of the by-
product. The reduced yield of pinacol for this experiment
is expected because the ketyl radical anions have smaller
chance to find an unreduced ketone molecule with which
it can react.
Table Comparison of the Effect of Supporting Electrolytes and Sol-
vent in the Electrochemical Carboxylation of Methyl Aryl Ketones 1
and 2a
Entry
Solvent
Yield (%)b
Supporting
Electrolyte
1a
2a
79
67
75
61
72
61
40
34
1
Bu4NBr
Et4NBr
NaBr
DMF
84
64
78
60
67
54
46
40
MeCN
DMF
2
3
4
MeCN
DMF
MeCN
DMF
KBr
The nature of the supporting electrolyte seems to have an
important influence on the selectivity of the desired prod-
uct. Among various kinds of supporting electrolytes, tet-
rabutylammonium bromide is found to be the most
effective one in improving the yield of 1a and 2a in our
system. Tetraethylammonium bromide was slightly less
MeCN
a Electrolysis of 1 and 2 were carried out at 5 °C in the presence of at-
mospheric pressure of carbon dioxide with a platinum cathode and
magnesium anode at 10 mA/cm2.
b Isolated yields.
Synthesis 2002, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York

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Electrochemical Carboxylation of Methyl Aryl Ketones
401
Scheme 2
Scheme 3
stable magnesium carboxylate, which upon acid treatment lowed by the addition of a second electron. Typical cyclic
gives carboxylic acid. For an efficient electrochemical voltammogarm of this is shown in the Figure and the elec-
carboxylation, both the cathodic reduction of methyl aryl tron distribution of radical anion in the presence of carbon
ketones and the anodic dissolution of magnesium metal dioxide is shown in Scheme 3. In this proposed mecha-
must occur at the same time in the same cell.
nism, the reaction begins with the formation of ketyl rad-
ical by one-electron reduction of starting ketone. Thus -
hydroxy carboxylic acid has been obtained by successive
carboxylation followed by addition of a second electron
and protonation confirming the number of electrons trans-
ferred to the starting material upon addition of carbon di-
oxide as two.
Probable reaction pathways of the present electrochemi-
cal carboxylations are shown in Scheme 2.
Under the experimental conditions, the maximum yields
are obtained with Bu4NBr/DMF system and the effect of
solvent is larger for tetraalkylammonium salt supporting
electrolyte than for alkali metals.
On the basis of these experimental results, the electro-
chemical carboxylation of methyl aryl ketones may be
carried out conveniently for the laboratory production of
-hydroxy- -methyl carboxylic acids.
In the cyclic voltammetry of 4-acetylbiphenyl (2), the re-
duction peak is observed at –1.85 V versus Ag/AgCl at
hanging mercury drop electrode (HMDE) of an area 0.15
mm in DMF containing 0.1 M Bu4NBr at 0.2 V/s and the
reduction is irreversible indicating that the radical anion
reduction product of 2 is relatively stable and does not re-
act rapidly with components of the solution. Addition of
carbon dioxide to the solution causes an increase of ca-
thodic current, an anodic shift in peak potential and elim-
ination of the reverse anodic current. This indicates a very
fast reaction of radical anion of 2 with carbon dioxide fol-
Melting points were recorded with a Mel-Temp apparatus and are
uncorrected. IR spectra were obtained with a Perkin-Elmer 1600
1
spectrophotometer. H NMR was recorded on a Varian EM-360
spectrometer in CDCl3 in the presence of SiMe4 as an internal stan-
dard. The electrolyses measurements were carried out by using Po-
tentiostat (Model: PS-603). Cyclic voltammetries were measured
with a Metrohm unit 757VA computrace at HMDE and Ag/AgCl as
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J. Damodar et al.
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Anal. Calcd for C15H14O3 (242.3): C, 74.36; H, 5.82. Found: C,
74.29; H, 5.87.
Acknowledgement
One of the authors JD is thankful to Council of Scientific and Indu-
strial Research, New Delhi for providing financial support in the
form of Senior Research Fellowship.
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reference electrode. The compounds 1 and 2 are commercially
available. DMF was distilled over CaH2. Reagent grade tetraalky-
lammonium salts and metal halides were used as supporting electro-
lytes without further purification. Carbon dioxide used was 99%
pure. The products 1a and 2a were purified using column chroma-
tography.
-Hydroxy- -methylfluorene-2-acetic Acid (1a); Typical
Procedure
A mixture of 2-acetylfluorene (1; 1.2 g, 5 mmol) and 0.1 M Bu4NBr
in DMF (50 mL) was added into an undivided cell equipped with a
platinum cathode and a magnesium anode. The mechanically stirred
solution was electrolysed at about 5 °C at 10 mA/cm2 under a slow
stream of carbon dioxide until electricity of 2 F/mol was passed. Af-
ter electrolysis, the power supply was turned off and the solution
was transferred to a round-bottomed flask. The DMF was stripped
off in a rotatory evaporator followed by addition of H2O (40 mL).
The product was separated from aqueous solution by acidifying it
with HCl. The product was extracted with Et2O (150 mL) and dried
(MgSO4). Evaporation of solvent afforded 1 g (84%) of 1a; mp
175–176 °C (Lit.19 mp 176–178 °C).
IR (neat): 3300–2800, 1700 cm–1.
1H NMR (CDCl3): = 1.76 (s, 3 H), 7.00–7.40 (m, 7 H), 9.15 (s, 1
H), 11.5 (s, 1 H).
Anal. Calcd for C16H14O3 (254.3): C, 75.57; H, 5.55. Found: C,
75.66; H, 5.51.
-Hydroxy- -methylbiphenyl-4-acetic Acid (2a)
Electrochemical carboxylation of 4-acetylbiphenyl (2) under the
same procedure as that of 1 gave 0.79 g (79%) of 2a; mp 151–
152 °C.
IR (neat): 3400–2800, 1700 cm–1.
1H NMR (CDCl3): = 1.78 (s, 3 H), 6.9–7.4 (m, 9 H), 9.3 (s, 1 H),
11.7 (s, 1 H).
Synthesis 2002, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York