Synthesis of the ethyl esters of 4-(3-pyridyl)- and 4-(4-pyridyl)-2-oxobutenoic acids

Article abstract of DOI:10.1023/A:1015679118975

We have developed a method for the synthesis of ethyl 4-(3-pyridyl)- and 4-(4-pyridyl)-2-oxobutenoates by condensation of 3-pyridinecarbaldehyde and 4-pyridinecarbaldehyde monohydrate respectively with ethyl pyruvate, esterifiction of the target acids, and hydrolysis of the corresponding ethyl ester ketals in the presence of FeCl₃·6H₂O.

Full text of DOI:10.1023/A:1015679118975

Chemistry of Heterocyclic Compounds, Vol. 38, No. 3, 2002
SYNTHESIS OF THE ETHYL ESTERS
OF 4-(3-PYRIDYL)- AND 4-(4-PYRIDYL)-
2-OXOBUTENOIC ACIDS
Dz. Sile, V. A. Slavinska, G. Rozental, J. Popelis, Yu. Balodis, and E. Lukevics
We have developed a method for the synthesis of ethyl 4-(3-pyridyl)- and 4-(4-pyridyl)-2-oxobutenoates
by condensation of 3-pyridinecarbaldehyde and 4-pyridinecarbaldehyde monohydrate respectively with
ethyl pyruvate, esterifiction of the target acids, and hydrolysis of the corresponding ethyl ester ketals in
the presence of FeCl
3
·6H O.
2
Keywords: ketals, 3- and 4-pyridinecarbaldehydes, 2-oxobutenoate esters, ketal hydrolysis, aldehyde
condensations.
Ethyl 4-substituted 2-oxobutenoates are used in the synthesis of antihypertensive substances [1].
The compounds referred to are a promising starting material for the preparation of the corresponding
homo-α-amino acids, diamino acids, epoxides, and others [2].
The potassium salts of unsaturated α-keto acids are usually obtained by the condensation of aldehydes
with pyruvic acid in basic medium [3]. A drawback to this procedure is the contamination of the target
compound by the products of the reaction of pyruvic acid, which is of low stability upon storage and is difficult
to purify [4-6].
We have proposed a method for the preparation of the sodium salts of 4-substituted 2-oxobutenoic acids
by condensation of ethyl pyruvate with aldehydes in basic medium [5-8]. Under these reaction conditions
hydrolysis of the ester occurs and the pyruvic acid formed condenses with the aldehyde without undergoing
conversion to side products. In addition, there is a possible reaction of the pyruvate ester with the aldehyde and
subsequent hydrolysis of the ester of the corresponding butenoic acid. Using the proposed method we obtained
the sodium salts of 4-phenyl-2-oxobutenoic acid, 4-(2-furyl)-2-oxobutenoic acid, and 4-(2-thienyl)-2-
oxobutenoic acid in high yields and in high purity [5-8].
However, the condensation of 2-pyridinecarbaldehyde under the optimum conditions for the synthesis of
the corresponding butenoic acid derivatives containing 2-furyl-, phenyl-, and 2-thienyl radicals does not give
satisfactory results [5]. In these conditions, a strong tarring of the 2-pyridinecarbaldehyde occurs and it was not
possible to separate the target product from the reaction mixture. For the condensation of
3
-pyridinecarbaldehyde with ethyl pyruvate the yield of the sodium salt of the 4-(3-pyridyl)-2-oxobutenoic acid
was also comparatively low (not greater than 33%) [5]. There are no reports in the literature of the synthesis of
the sodium salt or other derivatives of 4-(4-pyridyl)-2-oxobutenoic acid.
In this work we propose a three stage method for the synthesis of ethyl 4-(3-pyridyl)- and 4-(4-pyridyl)-
-oxobutenoic acids according to the scheme:
2
_
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia; e-mail: dz.sile@osi.lv. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 321-325, March, 2002. Original article submitted
September 27, 2000.
0
009-3122/02/3803-0287$27.00©2002 Plenum Publishing Corporation
287

CHO
CH=CH–COCOONa
FeCl ·6H O
NaOH, H O
2
+
MeCOCOOEt
N
N
1
2
OEt
.
1
2
. H
CH=CH–C–COOEt
. EtOH, SOCl
2
3
2
OEt
CH Cl
2
2
N
3
CH=CH–CO–COOEt
N
4
a,b
a 3-pyridyl, b 4-pyridyl
Bearing in mind the high solubility of the sodium salts of 4-(3-pyridyl)- (2a) and 4-(4-pyridyl)-2-
oxobutenoic acids (2b) in polar solvents when compared with derivatives containing the phenyl, 2-furyl, or
2
-thienyl radicals we suggest carrying out the condensation of 3- (1a) and 4-pyridinecarbaldehydes (1b) with
ethyl pyruvate with a lower content of water in the reaction medium (molar ratio of ethyl pyruvate:
3
2
2
-pyridinecarbaldehyde:NaOH; water equal to 1:2:0.9:13.9). Under these conditions the yield of the sodium salt
a reaches 40% with a 98% purity of the target product and the sodium salt of 4-(4-pyridyl)-2-oxobutenoic acid
c is obtained in 36% yield.
Esterification of 4-(3-pyridyl)-2-oxobutenoic acid by ethanol in the presence of p-toluenesulfonic acid
or thionyl chloride occurs non selectively (see Table 1). A mixture of the ethyl ester and the full ketal of the
indicated acid is obtained.
In the condition used, the yields of the ethyl ester and the other products are lower than the yield of the
full ketal, that of the ethyl 4-(3-pyridyl)-2,2-diethoxybutenoate (3a) being 45%.
We have attempted to carry out the hydrolysis of the ketal 3a using phosphoric acid in a mixture of
water and acetonitrile [9] and CuCl
2
·H O [10]. However, under these conditions the hydrolysis occurs very
2
unsuccessfully. Better results were obtained when carrying out the hydrolysis of ketal 3a in the presence of
FeCl
3
·6H
2
O in CH
2
Cl solution [11]. Under optimum conditions, the yield of the ethyl 4-(3-pyridyl)-2-
2
oxobutenoate (4a) after hydrolysis of the ketal was 62%.
EXPERIMENTAL
1
H NMR spectra were measured on Varian Mercury-200B (200 MHz) and Bruker WH-90 DS (90 MHz)
instruments using CDCl
standard.
3
solvent and TMS or DSS (2,2-dimethyl-2-silapentane-5-sulfonic acid) as internal
GLC Analysis was performed on an HP-5890 chromatograph with flame ionization detector and a
quartz capillary column (0.53 mm × 25 m) with Permabond OV-1-DF-1.00 liquid phase, helium gas carrier, a
temperature program of 50-270°C at 10°C/min, and vaporizer and detector temperature of 270°C. A normalized
method of calculation was used.
Mass spectra were obtained on a Kratos MS-25 spectrometer with an ionization intensity of 70eV.
The starting materials were the ethyl pyruvate with a product purity not less than 97% (Fluka) and the
3
2
-pyridinecarbaldehyde and 4-pyridinecarbaldehyde monohydrate with a purity of not less than 97%.
88

TABLE 1. Synthesis of the Ethyl Esters of 4-(3-Pyridyl)- and 4-(4-Pyridyl)-2-oxobutenoic Acids
Reaction conditions
Yield, molar %
Unreacted starting
material, %
Molar ratio of
Reaction
Experiment
Starting material
Reagent or catalyst
starting material temperature, Reaction time, h
ketals 3a,b
target esters 4a,b
to reagent
1 : 3
°C
20
1
Sodium salt of 2-oxo-4-
SOCl2
25
36.5
6.2
—
(
3-pyridyl)butenoic acid 2a
2
3
4
5
6
7
8
− " −
− " −
− " −
− " −
− " −
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
1 : 5
1 : 5
1 : 5
1 : 5
1 : 5
1 : 1.4
1 : 1.4
20
20
20
20
20
80
50
22
16
6.5
3.5
23
6
39.3
23.5
21.8
12.6
45.8
4.5
12.5*
18.8
26.9
29.8
19.4
0.8
—
5.2
6.0
9.5
—
—
95.0
− " −
p-toluenesulfonic acid
− " −
Sodium salt of 2-oxo-4-
4
(
4-pyridyl)butenoic acid 2b
9
− " −
SOCl2
1 : 5
20
48
39.4
2.1
—
_
_____
*
NaHCO was used for the neutralization in the separation of the products.
3

Sodium Salt of 2-Oxo-4-(3-pyridyl)butenoic Acid (2a). A solution of NaOH (3.5 M, 30 ml) was
added gradually over 0.5 h to a mixture of 3-pyridinecarbaldehyde (25.7 g, 0.24 mol) and ethyl pyruvate (14.9 g,
0
.12 mol) cooled to 5°C. The product was stirred for 1 h at 5°C and then for 2 h at room temperature. Ethanol
(
70 ml) was added to the reaction mixture and it was left for 24 h at room temperature. The precipitated yellow
salt 2a was filtered off and washed on the filter (3 × 50 ml) with a mixture of ethanol and ether (1:1), then
2
× 50 ml of a mixture of ethanol, ether, and chloroform (1:0.5:0.5), and dried in air. The yield of the salt 2a
1
was 10 g (40%) with a purity of 98%. H NMR spectrum (DMSO-d
6
, TMS), δ, ppm, J (Hz): 6.93 and 7.49 (1H
and 1H, dd, J = 16.5, CH=CH); 7.43 (1H, m, J = 7.8 and J = 4.8, 5-HPy); 8.10 (1H, m, J = 7.8, 4-HPy); 8.56 (1H,
m, J = 4.8, J = 1.5, 6-HPy); 8.79 (H, m, J < 2, 2-HPy).
Sodium Salt of 2-Oxo-4-(4-pyridyl)butenoic Acid (2b). A solution of NaOH (3.5 M, 18 ml) was
added gradually over 20 min to a mixture of 4-pyridinecarbaldehyde monohydrate (10.11 g, 80.8 mmol) and
ethyl pyruvate (6.8 g, 58.6 mmol) cooled to 14°C with a solution pH of 9-10. The solution was stirred for 3 h at
room temperature and the precipitated yellow salt 2b was filtered off, washed with a small amount of ethanol,
and dried in air to give a substance (4.38 g) which contained the salt 2b (36%) with 97% purity. It was
1
recrystallized from water. H NMR Spectrum (D
2
O, DSS), δ, ppm, J (Hz): 7.06 and 7.60 (2H, dd, CH=CH,
J = 16.5); 7.55 (1H, d, J = 1.5, J = 5.4, 3-HPy). 7.60 (1H, d, J = 1.5, J = 5.4, 5-HPy); 8.53 (1H, d, J = 5.4, 2-HPy);
8
.55 (1H, d, J = 1.5, J = 5.4, 6-HPy).
Ethyl 2,2-Diethoxy-4-(3-pyridyl)butenoate (3a). SOCl (5.4 ml) was added dropwise to absolute
2
ethanol (52 ml) cooled to -8°C followed by the salt 2a (3 g, 15 mmol). The reaction mixture was stirred at room
temperature for 23 h until the starting material had disappeared and then evaporated. The residue was dissolved
in water (40 ml) and triethylamine (1 ml) was added to a solution pH of 5. The aqueous solution was extracted
with ethyl acetate (8 × 25 ml). After each extraction the solution pH was corrected by the addition of
triethylamine. The ethyl acetate extract was dried over anhydrous Na
2
SO
4
and evaporated to give a dark oil
+
(
[
4.28 g) which contained compound 3a (1.89 g, 45%). Mass spectrum, m/z (%): 250 (2) [M-C
H
2 5
] ; 234 (8)
+
+
+
+
M-OC
2
H
5
] ; 206 (77) [M-COOC
2
H
5
] ; 150 (100) [M-COOC
2
H
5
-2C
2
H
4
] ; 132 (64) [Py–CH=CH–CO] ;
+
+
1
04 (30) [M-C(OC
2 5
H )
2
-COOC H
2 5
] ; 78 (13) [Py] ; and 0.16 g (18%) of ethyl 2-oxo-4-(3-pyridyl)butenoate 4a
+
+
+
(
[
mass spectrum, m/z (%): 205 (3) [M] ; 177 (4) [M-C
H
2 4
] ; 132 (100) [M-COOC
2
H
5
] ; 104 (33)
+
+
M-COCOOC
2
H
5
] ; 78 (14) [Py] ).
Ethyl 2,2-Diethoxy-4-(4-pyridyl)butenoate (3b). SOCl
2
(1.08 ml) was added to absolute ethanol
(
10 ml) cooled to -8°C followed by the salt 2b (0.6 g, 3 mmol). The reaction mixture was stirred at room
temperature for 48 h until the starting material had disappeared and then evaporated. The residue was dissolved
in water (20 ml) and triethylamine was added to a solution pH of 5-6. The product was extracted with ethyl
acetate (5 × 10 ml), the extract dried over anhydrous Na
2
SO , and evaporated to give a dark oil (0.52 g) which
4
contained the ethyl ester 3b (0.26 g, 31%) (the solution after extraction of ester 3b contained a mixture of
+
+
unidentified products. Mass spectrum, m/z (%): 250 (1) [M-C
2
H
5
] ; 234 (8) [M-OC
2
H
5
] ; 206 (72)
+
+
+
[
[
M-COOC
M-COOC
2
H
5
] ; 178 (17) [M-COOC
2
H
5
-C
2
H
4
] ; 150 (60) [M-COOC
2
H
5
-(C
2
H
4
)
2
] ; 132 (100)
+
+
+
2
H
-(C H
5 2 5
)
2
] ; 104 (21) [Py–CH=CH] ; 78 (16) [Py] .
Ethyl 2-oxo-4-(3-pyridyl)butenoate (4a). FeCl
3
·6H
2
O (0.8 g) was added to a solution of 0.30 g of the
Cl
O was added and refluxed for a
(20 ml) was added and it was
mixture obtained in experiment 3 which contained the ketal 3a (0.135 g) and the ester 4a (0.093 g) in CH
5.5 ml), the product was refluxed for 20 min and a further 0.8 g of FeCl ·6H
further 20 min. At the end of the reaction a saturated solution of NaHCO
2
2
(
3
2
3
extracted with ethyl acetate (4 × 20 ml). The extract was washed with NaCl solution and dried over anhydrous
Na
2
SO
4
. The ethyl acetate was evaporated to dryness and the residue of yellow material (0.180 g) was
1
recrystallized from hexane to give the ethyl ester 4a (0.121 g, 62.5% yield, 98% purity); mp 51-52°C. H NMR
spectrum (CDCl
.49 (2H, d and d, J = 15.2, CH=CH); 8.05 (1H, dt, 4-HPy); 8.73 (1H, dd, 6-HPy); 8.91 (1H, d, 2-HPy). Found, %:
C 64.37; H 5.38; N 6.75. C11 . Calculated, %: C 64.36; H 5.40; N 6.85.
3
, TMS), δ, ppm, J (Hz): 1.46 (3H, t, CH
3
); 4.46 (2H, q, CH ); 7.47 (1H, dd, 5-HPy); 7.91 and
2
7
H11NO
3
2
90

Ethyl 2-oxo-4-(4-pyridyl)butenoate (4b). FeCl
the crude mixture (0.26 g) from experiment 4 (which contained the ethyl ester 3b (0.17 g)), in CH
and then refluxed for 20 min. FeCl ·6H O (0.6 g) was further added twice and after the addition of each new
portion the solution was refluxed for 20 min. A saturated solution of NaHCO (18 ml) was then added and the
SO and evaporated. The
3
·6H
2
O (0.6 g) was added with stirring to a solution of
2
Cl (5 ml)
2
3
2
3
product was extracted with ethyl acetate (4 × 20 ml). The extract was dried over Na
2
4
yellow residue (0.093 g) was recrystallized from hexane to give compound 4b (0.066 g, 53% yield, 97% purity)
1
with mp 53-54°C. H NMR spectrum (CDCl
3
, TMS), δ, ppm, J (Hz): 1.41 (3H, t, CH
3
); 4.40 (2H, q, CH ); 7.46
2
(
2H, m, J = 6.0, 3,5-HPy); 7.50 and 7.76 (2H, d and d, J = 16.2, CH=CH); 8.70 (2H, m, J = 6.0, 2,6-HPy).
Found, %: C 64.33; H 5.39; N 6.71. C11
H
11NO . Calculated, %: C 64.36; H 5.40; N 6.85.
3
This work was carried out with the financial support of the Latvian Council for Science (grant No. 696).
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91