Hydrogenation of ethyl esters of 4-phenyl- and (2-furyl)-substituted 2,4-dioxobutyric acids at palladium black

Article abstract of DOI:10.1007/s10593-006-0128-9

The hydrogenation of ethyl 4-R-2,4-dioxobutyrates (R = phenyl, 2-furyl) at 5% Pt/Al₂O₃ catalyst, modified with cinchonidine, and at palladium black was investigated. The former had low activity under the conditions we tested. The mai

Full text of DOI:10.1007/s10593-006-0128-9

Chemistry of Heterocyclic Compounds, Vol. 42, No. 5, 2006
HYDROGENATION OF ETHYL ESTERS
OF 4-PHENYL- AND (2-FURYL)-SUBSTITUTED
2,4-DIOXOBUTYRIC ACIDS AT PALLADIUM BLACK
V. Slavinska, Dz. Sile, G. Rozenthal, G. Maurops, J. Popelis, M. Katkevich, V. Stonkus,
and E. Lukevics
The hydrogenation of ethyl 4-R-2,4-dioxobutyrates (R = phenyl, 2-furyl) at 5% Pt/Al2O3 catalyst,
modified with cinchonidine, and at palladium black was investigated. The former had low activity under
the conditions we tested. The main products during the hydrogenation of these compounds at palladium
black are ethyl 4-R-2-hydroxy-4-oxobutyrates. The yield of the phenyl derivative amounts to 68.5%,
while the yield of the corresponding 2-furyl derivative amounts to 97%. In the last case ethyl 2-hydroxy-
4-oxo-4-(2-tetrahydrofuryl)butyrate was detected as impurity. The optimum conditions for the formation
of ethyl 2-hydroxy-4-phenylbutyrate (yield 88.2%) were determined.
Keywords: ethyl 4-substituted 2,4-dioxobutyrates, platinum and palladium catalysts, hydrogenation.
The derivatives of 4-substituted 2-hydroxybutyric acids are valuable synthons for the production of
antihypertensive substances, homoamino acids, hydroxamic acids, and other compounds [1, 2].
We studied the hydrogenation of sodium 2-oxo-4-phenyl-, 4-(2-furyl)-2-oxo-, 2-oxo-4-(2-thienyl)-, and
2-oxo-4-(3-pyridyl)butenoates at nickel and palladium catalysts.
During the hydrogenation of sodium 2-oxo-4-phenylbutenoate at nickel catalysts the corresponding salt
of 2-hydroxy-4-phenylbutyric acid is formed [3].
The use of palladium black and 10% Pd/C catalyst leads to the formation of sodium 2-oxo-4-
phenylbutyrate. During the hydrogenation of sodium 4-(2-furyl)-2-oxobutenoate at Raney nickel catalyst the
corresponding 4-(2-furyl)-2-oxobutyrates and 4-(2-furyl)-2-hydroxybutyrates and aliphatic compounds from
hydrogenolysis of the molecule of the original compound are formed [4].
During the hydrogenation of sodium and ethyl 2-oxo-4-(2-thienyl)butenoates at Raney nickel the
corresponding derivatives of 2-oxo-4-(2-thienyl)butyric acid and 2-hydroxy-4-(2-thienyl)butyric acid are formed
[5]. Palladium catalysts secure the more selective formation of the corresponding oxo compound than Raney
nickel. The formation of ethyl 2-oxo-4-(2-tetrahydrothienyl)butyrate in addition to the above-mentioned
compounds was also observed during the hydrogenation of ethyl 2-oxo-4-(2-thienyl)butenoate at palladium
black.
During the hydrogenation of sodium 2-oxo-4-(3-pyridyl)butenoate at palladium black the reaction
products were sodium 2-oxo-4-(3-pyridyl)butyrate and 2-hydroxy-4-(3-pyridyl)butyrate and hydrogenolysis
products. The reaction takes place by a parallel–consecutive mechanism [6].
During the hydrogenation of derivatives of 4-substituted 2-oxobutenoic acids the double bond is
saturated, and the carbonyl group is partly hydrogenated. The latter depends on the composition of the catalyst
and on the structure of the initial compound.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga; e-mail: dzsile@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 5, pp. 655-659, May, 2006. Original article submitted March 30, 2005.
570
0009-3122/06/4205-0570©2006 Springer Science+Business Media, Inc.

The second direction for the synthesis of the synthons [the (R)-enantiomers of the respective 2-
hydroxybutyric esters] for the production of antihypertensive products and other biologically active substances is
hydrogenation of the esters of 4-substituted 2,4-dioxobutyric acids [7]. These compounds are more readily
obtainable than the corresponding derivatives of butenoic acids.
In this case hydrogenation takes place in two stages:
Pt/Al2O3
Pd/C
R–C(O)CH2C(O)COOEt
R–C(O)CH2CH(OH)COOEt
2a,b
1a,b
R–CH2CH2CH(OH)COOEt
3a
1-3 a R = Ph; 1, 2 b R = 2-furyl
At the first stage hydrogenation of the 4-substituted 2,4-dioxobutyric esters 1 occurs under mild
conditions, and the corresponding 2-hydroxy compounds 2 are obtained. The enantiomers are separated by
crystallization, and the R isomer is hydrogenated under more drastic conditions to the esters of 4-substituted
2-(R)-hydroxybutyric acids 3.
We studied the hydrogenation of ethyl 4-phenyl-2,4-dioxobutyrate (1a) and 4-(2-furyl)-2,4-dioxo-
butyrate (1b) at palladium black and Pt/Al2O3. (The reaction conditions are given in Table 1.)
Under the conditions recommended in [8] the 5% Pt/Al2O3 catalyst modified with
10,11-dihydrocinchonidine is characterized by low activity. (The conversion of the raw material does not exceed
17%.) During the hydrogenation of compounds 1a and 1b at palladium black at room temperature with a
TABLE 1. The Hydrogenation of Ethyl 4-Substituted 2,4-Dioxobutyrates
1a,b*
Reactions
products
Com-
pound
сin of 1,
mol/l
Time
reaction, h
Unreacted 1a,b,
Catalyst*2
%
2
3а
1a
5% Pt/Al2O3
Pd black
0.303
0.182
0.061
0.062
0.27
3
4
5.5
—
—
88.2
—
83.0
—
Pd black
0.5
0.3
4
68.5
38.5
4.6
9.6
45.5
84.0
—
Pd black
5% Pt/Al2O3
Pd black
—
—
1b
0.06
1
96.6
88.4*3
—
Pd black
0.06
4
—
—
_______
* At 5% Pt/Al2O3, modified with 10,11-dihydrocinchonidine (catalyst–
modifier, 10:1), in toluene (H pressure 60 atm) and Pd black in ethanol
(H pressure 1 atm) at room temperature.
*2 Before use the 5% Pt/Al2O3 catalyst was activated in a stream of hydrogen
at 400°C for 2 h. After activation it was cooled and quickly transferred to the
reaction flask, the 10,11-dihydrocinchonidine and the initial substance were
added, and the hydrogenation was performed.
*3 Ethyl 2-hydroxy-4-oxo-4-(2-tetrahydrofuryl)butyrate was detected in the
catalyzate by chromatography (yield ~5%). Mass spectrum, m/z (I, %):
216 [M]+ (4); 143 [M–COOC2H5]+ (4); 125 (3); 71 [3CH2–O–CH]+ (100);
43 (54).
571

hydrogen pressure of 1 atm in ethanol solution the first reaction products are ethyl 2-hydroxy-4-oxo-4-
phenylbutyrate (2a) (yield 68.5%) and ethyl 4-(2-furyl)-2-hydroxy-4-oxobutyrate (2b) (yield up to 97% with
total conversion of the raw material). In the last case small amounts of ethyl 2-hydroxy-4-oxo-(2-
tetrahydrofuryl)butyrate are found as impurities.
During prolonged hydrogenation of the ester 1a (4 h) with the initial compound at a concentration of
0.182 M (ratio of initial compound and catalyst 1:0.5) in ethanol solution ethyl 2-hydroxy-4-phenylbutyrate (3a)
(yield 88.2%), which was not observed during the hydrogenation of compound 1b, was obtained.
Thus, the first stage in the production of the (R)-enantiomers of the of the respective 4-substituted
2-hydroxybutyric esters can be realized under mild conditions with palladium black.
EXPERIMENTAL
The initial substances were obtained by the method in [9]: 1a by the condensation of acetophenone with
diethyl oxalate, and compound 1b by the condensation of 2-acetylfuran with diethyl oxalate. The contents of the
main products were 98 and 99% respectively. The catalyst 5% Pt/Al2O3 (supplied by Acros) was modified with
10,11-dihydrocinchonidine by the method in [10].
The initial substances and the reaction products were determined by HPLC on Rainin chromatographic
apparatus; Dynamax-300A analytical column (4.6×250 mm), C8 reverse phase at λ 220 nm; eluant 34%
acetonitrile in 0.25 N triethylammonium phosphate. The esters 2a,b were purified for analytical purposes on a
Buchi preparative chromatograph, 26×470 mm column filled with Silasorb C18 sorbent. The eluant was
acetonitrile, 0.1% trifluoroacetic acid.
1
The H NMR spectrum of compound 3a was recorded on a Bruker WH-90 spectrometer (90 MHz) in
CDCl3, internal standard TMS. The 1H NMR spectra of the esters 2a and 2b were recorded on a Varian Mercury-
200 BB spectrometer (200 MHz) with TMS as internal standard.
The mass spectra were obtained on a Kratos MS-25 chromato-mass spectrometer at 70 eV.
Hydrogenation of Ethyl 2,4-Dioxo-4-phenylbutyrate 1a in the Presence of Pt/Al2O3 Modified with
10,11-Dihydrocinchonidine. In an autoclave we placed compound 1a (1.88 g, 8.54 mmol), dissolved in toluene
(30 ml). We added 10,11-dihydrocinchonidine (0.005 g) and 5% Pt/Al2O3 (0.05 g) catalyst that had been
previously activated at 400°C for 2 h in a stream of hydrogen. The mixture was hydrogenated at a hydrogen
pressure of 60 atm at room temperature. At the end of the reaction the catalyst was filtered off, and the catalyzate
was evaporated. We obtained 1.80 g of the product, which contained 0.11 g of the ester 2a (yield 5.8%) and
83.0% of the unreacted initial substance.
Hydrogenation of Ethyl 2,4-Dioxo-4-phenylbutyrate (1a) in the Presence of Pd Black. A. We
dissolved the ester 1a (0.60 g, 2.73 mmol) in ethanol (45 ml), added moist palladium black (0.3 g), and
hydrogenated the mixture at atmospheric pressure at room temperature. At the end of the reaction the catalyst
was filtered off, and the catalyzate was evaporated. We obtained 0.54 g of the product, which contained 0.06 g
of the unreacted initial compound (9.6%) and 0.42 g of the ester 2a (yield 68.5%). 1H NMR spectrum, δ, ppm (J,
Hz): 1.18 (3H, t, J = 7.2, CH3); 3.37 (2H, d, J = 6.2, CCH2C); 4.10 (2H, q, J = 7.2, OCH2); 4.54 (1H, t, J = 6.2,
CHO); 5.7 (1H, br. s, OH); 7.4-7.7 (5H, m, C6H5).
B. We dissolved the ester 1a (0.06 g, 2.73 mmol) in ethanol (15 ml) and added moist palladium black
(0.3 g). The mixture was hydrogenated for 4 h at atmospheric pressure and room temperature. At the end of the
reaction the catalyst was filtered off, and the catalyzate was evaporated. We obtained 0.52 g of the product,
1
which contained 0.50 g of the ethyl ester 3a (yield 88.2%). H NMR spectrum, δ, ppm (J, Hz): 1.19 (3H, t,
J = 7.6, CH3); 1.88 (2H, m, C–CH2–C); 2.65 (2H, t, J = 8.0, Ph–CH2); 3.98 (1H, m, CH–O); 4.07 (2H, q, J = 7.6,
OCH2); 4.2 (1H, br. s, OH); 7.23 (5H, m, C6H5).
572

Hydrogenation of Ethyl 4-(2-Furyl)-2,4-dioxobutyrate 1b in the Presence of Pt/Al2O3 Modified
with 10,11-Dihydrocinchonidine. In an autoclave we placed the ester 1b (1.68 g, 8.00 mmol), dissolved in
toluene (29.6 ml), and we added 10,11-dihydrocinchonidine (0.008 g) and 5% Pt/Al2O3 catalyst (0.08 g) that had
been previously activated at 400°C for 2 h in a stream of hydrogen. The mixture was hydrogenated for 3 h
30 min at a hydrogen pressure of 60 atm and at room temperature. At the end of the reaction the catalyst was
filtered off, and the catalyzate was evaporated. We obtained 1.52 g of the product, which contained 0.08 g of the
ester 2b (yield 4.6%) and 1.41 g of the unreacted ester 1b.
Hydrogenation of Ethyl 4-(2-Furyl)-2,4-dioxobutyrate (1b) in the Presence of Pd Black. We
dissolved the ester 1b (0.5 g, 2.38 mmol) in ethanol (40 ml) and added moist palladium black (0.3 g). The
mixture was hydrogenated with molecular hydrogen for 1 h at atmospheric pressure and room temperature. At
the end of the reaction the catalyst was filtered off, and the catalyzate was evaporated. We obtained 0.50 g of the
product, which contained 0.49 g of the ester 2b (yield 96.6%). 1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J
= 7.1, CH3); 3.30 and 3.39 (2H, AB part of ABM system, J = 7.0, J = 6.4, J = 4.4, C–CH2–C); 4.26 (2H, q, J =
7.1, OCH2); 4.65 (1H, M part of ABM system, J = 6.4, J = 4.4, CHOH); 5.7 (1H, br. s, COH); 6.55 (1H, dd, J =
3.6, J = 1.8, H-4 of furan); 7.24 (1H, dd, J = 3.6, J = 0.9, H-3 of furan); 7.61 (1H, dd, J = 1.8, J = 0.9, H-5 of
furan).
The work was financed by the Latvian Science Council (Grant No. 188).
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