Process for the preparation of substituted glyoxylic acid derivatives

A process for preparing substituted glyoxylic acid derivatives by oxidizing with a molecular oxygen containing gas an amide or ester of a hydroxy acid in the presence of a catalytic amount of a cobalt compound.

This invention relates to a process for the preparation of substituted 
glyoxylic acid derivatives by the oxidation of the corresponding hydroxy 
derivative. 
An example of such a reaction known in the art is the oxidation of a 
mandelic acid ester to the corresponding ester of phenylglyoxylic acid, 
which oxidation can be carried out with selenium dioxide or lead 
tetra-acetate as the oxidant (see page 127 of RODD's Chemistry of Carbon 
Compounds, 2nd edition, volume III part E, 1974, Elsevier Scientific 
Publishing Company). Another oxidant also known in the art for said 
oxidation is chromium trioxide (see European patent application 
0.006.539). 
A major disadvantage from the use of these above-mentioned oxidants is that 
a large amount of the metal compound is left over as waste. 
The present invention now provides an improved process for the preparation 
of substituted glyoxylic acid derivatives in which no metal compound is 
obtained as waste. 
The process according to this invention is distinguished by the features 
that, in combination, an amide or ester of a hydroxy acid of the general 
formula: 
##STR1## 
wherein R represents an (possibly substituted) aryl or heteroaryl group, 
is oxidized in the liquid phase, in the presence of cobalt as catalyst, 
with a molecular-oxygen-containing gas, and recovering from the reaction 
mixture the corresponding amide or the corresponding ester of a glyoxylic 
acid of the general formula: 
##STR2## 
wherein R has the above-mentioned meanings. 
It has now been found that the oxidation according to this invention can be 
carried out more rapidly than the oxidation in which the above-mentioned 
already known oxidants are employed, while, moreover, a higher degree of 
selectivity can be achieved. Furthermore, the product obtained is often 
pure enough to be suitable as such for further conversions, for instance, 
to an herbicide. 
The favorable result of the process according to this invention is very 
surprising. The fact is that, if either the nitrile of the hydroxy acid or 
the hydroxy acid itself is oxidized in the same manner, a reaction mixture 
is obtained in which the desired keto compound is not at all, or hardly at 
all, present. 
In the oxidation process according to this invention, various compounds may 
be used as starting materials. For instance, the aryl or heteroaryl 
(resonating heterocyclic radicals) group represented by R in the above 
general formula may be a phenyl, naphthyl, pyridyl, furyl or thienyl 
group, which groups can optionally be substituted with, for instance, one 
or more substituents from the group consisting of Cl, NO.sub.2, alkoxy of 
from 1-8 carbon atoms and alkyl of from 1-8 carbon atoms. 
Various esters can be employed as the ester of the hydroxy acid, for 
instance, those esters having, in the ester group, an alkyl group with 
from 1-8 carbon atoms, a cycloalkyl group with from 5-8 carbon atoms in 
the ring, a phenyl group or a naphthyl group. Alternatively, an amide may 
be used. 
In employing the process according to this invention, the oxidation takes 
place in the liquid phase. If the compound to be oxidized can function as 
a solvent for the reaction mixture, the oxidation can in principle be 
carried out without solvent. Preferably, however, a solvent is used. 
Suitable solvents include saturated aliphatic monocarboxylic acids with 
from 2-8 carbon atoms, especially acetic acid. The acid employed as 
solvent may be only of a commercial grade and contain, for instance, 3% by 
weight of water. Esters of the said acids can also be used as solvents. 
The quantity of solvent may also vary. A quantity of solvent of from 
0.5-15 g per gram of hydroxy derivative to be oxidized is very suitable. 
The catalytic quantity of cobalt required in the reaction mixture can be 
obtained by introduction of a cobalt compound soluble in the reaction 
mixture, such as inorganic or organic cobalt salts, or by the formation of 
such a compound in situ. Preferably, a cobalt salt of a saturated 
aliphatic monocarboxylic acid with from 1-8 carbon atoms, specifically 
cobalt acetate (either di- and/or tetravalent cobalt), is dissolved in the 
reaction mixture, for instance, in a quantity corresponding with from 1-50 
g cobalt per mole of compound to be oxidized. A very good result can be 
obtained if, in addition to the cobalt salt, an alkali metal bromide, is 
also present as a promoter in a quantity of, for instance, 0.5-20 g 
bromide per mole of compound to be oxidized. The catalyst and the promoter 
can be separated from the reaction mixture obtained, recycled, and be used 
again if so desired. 
The oxidation according to the invention can be carried out at various 
temperatures, for instance, from 25.degree. to 250.degree. C. Preferably, 
the chosen temperature is between about 70.degree. and about 150.degree. 
C. The pressure as such as not critical. Use of a pressure higher than 
atmospheric pressure may be of advantage in large scale oxidations, for 
instance if acetic acid is used as solvent and air as the 
oxygen-containing gas. The fact is that in such a case the explosive range 
of the acetic acid vapor-nitrogen-oxygen system can be avoided by diluting 
the air with nitrogen or by employing a pressure higher than atmospheric. 
The oxidation according to this invention can generally be carried out by 
methods known in the art for carrying out liquid phase oxidations with a 
molecular oxygen-containing gas. For instance, the gas may be passed 
through the reaction mixture for some time at the desired temperature, 
while the mixture is well stirred. In this process, different times may be 
chosen during which the reaction conditions are maintained.

The oxidation according to the invention will now be further elucidated in 
the following non-limiting Examples. 
EXAMPLE I 
Into a cylindrical reaction vessel with a capacity of 250 ml, provided with 
4 baffle plates, stirrer, reflux condenser and air inlet tube, 4 g of 
cobalt(II) acetate.4H.sub.2 O, 0.41 g of sodium bromide, 17 g of ethyl 
mandelate (0.094 mole) and 116 ml of acetic acid (99.5% by weight) were 
introduced. 
The reaction mixture was heated to 90.degree. C., after which air was 
passed in at a rate of 20.5 liters per hour. After the air had been passed 
in for 5 minutes, the temperature of the reaction mixture was 103.degree. 
C. After air had been passed in for 25 minutes, the temperature of the 
reaction mixture was 97.degree. C., and the introduction of the air was 
discontinued. 
The reaction mixture thus obtained was subjected to a gas chromatographic 
analysis, which showed that the ethyl mandelate had been completely 
converted into the corresponding keto compound, with a selectivity of 96%. 
The reaction mixture was subsequently poured out into 1 liter, of water, 
and the aqueous solution obtained was extracted with ether. The ether 
extract was neutralized with NaHCO.sub.3 to a pH of about 8 and dried over 
MgSO.sub.4. After evaporation of the ether under reduced pressure, 15.7 g 
light yellow product remained, which was the desired keto compound with a 
purity of 99% as determined by gas chromatographic analysis. The yield was 
92% of theoretical. 
COMATIVE EXAMPLES 
In the same way as described in Example I, an attempt was made to oxidize 
mandelic acid per se. After air had been passed through for 2 hours and 15 
minutes, the reaction mixture was analyzed, which showed that the mandelic 
acid had not been converted. 
An attempt to oxidize the nitrile of mandelic acid 
(benzaldehyde-cyanohydrin) in the manner as described in Example I also 
failed to result in a keto compound. After air had been passed through for 
15 minutes, the reaction mixture was found to contain, beside the initial 
product, benzaldehyde only, while, after air had been passed through for 1 
hour, benzoic acid had been formed as well. 
EXAMPLE II 
In the manner as described in Example I, 16.6 g methyl mandelate (0.1 mole) 
was oxidized. After air had been passed in for 1 hour, a 100% conversion 
was reached, at a selectivity of 94%. 
EXAMPLE III 
Example I was repeated. The reaction temperature, however, was kept at 
90.degree. C. After air had been passed through for 33 minutes, a 100% 
conversion was found to have been reached, and the selectivity was 98%. 
EXAMPLE IV 
Repetition of Example I at a temperature of 110.degree. had as a result 
that, after air had been passed through for 22 minutes, a 100% conversion 
had already been reached, and the selectivity was 98%. 
EXAMPLE V 
In the same way as described in Example I, 0.1 mole of mandelic acid amide 
was oxidized. After air had been passed through for 30 minutes, the 
conversion was 100% and the selectivity with respect to the corresponding 
keto-amide 81%. 
EXAMPLE VI 
In the manner as described in Example I, 0.25 mole ethyl mandelate was 
oxidized in 116 ml acetic acid with 4 g cobalt(II)acetate.4H.sub.2 O and 
0.41 g NaBr at a temperature of 100.degree. C. After a period of 75 
minutes, a conversion of 100% was reached, with the selectivity being 98%. 
EXAMPLE VII 
Example VI was repeated, except that NaBr was omitted. The oxidation 
process was much slower now. After 75 minutes, the conversion was 45% and 
the selectivity 81%. 
EXAMPLE VIII 
In the manner described in Example I, 18 g ethyl mandelate (0.1 mole) was 
oxidized. After air had been passed through for 30 minutes, the conversion 
was 100%, and the reaction mixture obtained was further processed as 
follows: 
First, the acetic acid was distilled off under reduced pressure. 
Subsequently, 100 g water was added to the remaining residue, and the 
mixture was subjected to extraction with ether. The organic layer obtained 
in this process was washed with water and neutralized with NaHCO.sub.3 to 
a pH of 8. After drying of the organic layer over MgSO.sub.4, the ether 
was evaporated under reduced pressure. 17.3 g of the desired keto ester 
compound was obtained (yield 95%), which, according to a gas 
chromatographic analysis, had a purity of 98.6%. 
EXAMPLE IX 
The aqueous layer obtained in Example VIII during the extraction with 
ether, which layer contained the cobalt catalyst and the NaBr, was 
evaporated to dryness. To the residue of 4.7 g 18 g ethyl mandelate (0.1 
mole) and 116 ml acetic acid (99.5% by weight) were added, after which the 
ethyl mandelate was oxidized in the manner described in Example I. After 
air had been passed through for 45 minutes, the reaction mixture was 
further processed in the manner described in Example VIII. 17.3 g keto 
compound was obtained (yield 92%), which as determined by a gas 
chromatographic analysis, had a purity of 95%. This shows the re-use of 
the cobalt catalyst and NaBr. 
EXAMPLE X 
In the manner described in Example I, 0.1 mole 2,4-dichloroethylmandelate 
was oxidized. After air had been passed through for 20 minutes, the 
conversion was 100% and the selectivity with respect to the desired keto 
compound was 93%. The keto compound obtained had a boiling point of 
118.degree. C. at a pressure of 27 Pa. 
EXAMPLE XI 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
4-methoxy-mandelic acid was oxidized. After air had been passed through 
for 20 minutes, the conversion was 100% and the selectivity with respect 
to the keto compound was 97%. 
EXAMPLE XII 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
(2-thienyl)hydroxyacetic acid was oxidized. After air had been passed 
through for 30 minutes, a conversion of 100% was reached. After further 
processing of the reaction mixture, 16.4 g product was obtained containing 
96% of the corresponding keto compound (yield 87%). 
EXAMPLE XIII 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
(3-pyridyl)hydroxyacetic acid was oxidized. After air had been passed 
through for 2 hours and 20 minutes, the conversion was 97% and the 
selectivity with respect to the relative keto compound was 82%. The keto 
compound obtained had a boiling point of 90.degree. C. at a pressure of 7 
Pa. 
EXAMPLE XIV 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
4-nitromandelic acid was oxidized. After air had been passed through for 2 
hours, a conversion of 96% was reached. The selectivity with respect to 
the relative keto compound was 60%. As by-product, the reaction mixture 
was found to contain 4-nitrobenzoic acid. 
EXAMPLE XV 
In the manner described in Example I, 0.1 mole of n-butyl mandelate was 
oxidized. After air had been passed through for 15 minutes, 100% 
conversion was reached. The selectivity with respect to the corresponding 
keto compound was 97%. 
EXAMPLE XVI 
In the manner described in Example I, 0.1 mole of the methyl ester of 
4-carbomethoxy mandelic acid was oxidized. After air had been passed 
through for 40 minutes, 100% conversion was reached. The selectivity with 
respect to the corresponding keto compound was 93%. 
EXAMPLE XVII 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
4-ethoxy mandelic acid was oxidized. After air had been passed through for 
30 minutes, 100% conversion was reached. The selectivity with respect to 
the desired keto compound was 92%. 
EXAMPLE XVIII 
In the manner described in Example I, 0.1 mole of the ethyl ester of 
3-phenoxy mandelic acid was oxidized. After air had been passed through 
for 30 minutes, 100% conversion was reached. The selectivity with respect 
to the desired keto compound was 98%. 
EXAMPLE XIX 
In the manner described in Example I, 0.1 mole ethyl mandalate in 116 ml 
acetic acid was oxidized at a temperature of 100.degree. C. with the aid 
of 2.7 g CoBr.sub.2.6H.sub.2 O. 
After air had been passed through for 35 minutes, 100% conversion was 
reached. The selectivity with respect to the keto compound concerned was 
94%.