Polyfunctional pyrazoles. 3. Synthesis of 3-(3-aryl-4-formyl-1-pyrazolyl) propionic acids and their amides

Article abstract of DOI:10.1007/s10593-005-0054-2

3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids were synthesized by the reaction of 3-aryl-1-(2-cyanoethyl)-4-formylpyrazoles with concentrated hydrochloric acid. They were converted into the corresponding amides by the carbodiimide method.

Full text of DOI:10.1007/s10593-005-0054-2

Chemistry of Heterocyclic Compounds, Vol. 40, No. 10, 2004
POLYFUNCTIONAL PYRAZOLES.
3.* SYNTHESIS OF 3-(3-ARYL-4-FORMYL-
1-PYRAZOLYL)PROPIONIC ACIDS AND THEIR AMIDES
M. K. Bratenko1, V. A. Chornous1, and M. V. Vovk2
3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids were synthesized by the reaction of 3-aryl-1-(2-
cyanoethyl)-4-formylpyrazoles with concentrated hydrochloric acid. They were converted into the
corresponding amides by the carbodiimide method.
Keywords: amides, dicyclohexylcarbodiimide, 3-(4-formyl-1-pyrazolyl)propionic acids, 1-(2-cyanoethyl)-
4-formylpyrazoles, hydrolysis.
Earlier [2] we described the synthesis of 3-aryl-1-(2-cyanoethyl)-4-formylpyrazoles and the
corresponding thiosemicarbazides. On the basis of the last reactions with monochloroacetic acid and maleic
anhydride unsymmetrical azines with 3-aryl-1-(2-cyanoethyl)-4-methylidenepyrazole and 2-thiazolidinylen-4-
one fragments having antimicrobial activity were obtained [3].
The present communication presents the results from selective modification of the 2-cyanoethyl
substituent in the 4-formylpyrazoles 1a-e to a 2-carboxyethyl substituent. We showed that during the action of
boiling concentrated hydrochloric acid the nitrile group of compounds 1a-e is readily hydrolyzed and forms
3-(3-aryl-4-formyl-1-pyrazolyl)propionic acids 2a-e with yields of 78-93%. It is remarkable that cleavage of the
C–N bond of neither the β-cyanoethyl nor the β-carboxyethyl substituent with the nitrogen atom of the pyrazole
ring was observed under the reaction conditions [4].
CHO
CHO
CHO
Ar
Ar
Ar
R1R2NH
DCC
H2O / HCl
CN
N
N
N
N
N
N
O
COOH
3a–e R2R1N
2a–e
1a–e
1, 2 а Ar = Ph, b Ar = 4-FC6H4, c Ar = 4-ClC6H4, d Ar = 4-BrC6H4, e Ar = 4-MeOC6H4;
3a,b,d-g R1 = H, c R1R2 = (CH2)2O(CH2)2; a Ar = Ph, R2 = 2-methyl-5-quinolinyl;
b Ar = 4-FC6H4, R2 = 4-MeOC6H4; c Ar = 4-FC6H4,; d Ar = 4-ClC6H4, R2 = 5-quinolinyl;
e Ar = 4-BrC6H4, R2 = 4-MeC6H4; f Ar = 4-BrC6H4, R2 = 3-pyridyl;
g Ar = 4-MeOC6H4, R2 = Ph
_______
* For Communication 2, see [1].
__________________________________________________________________________________________
1
Bukovinian State Medical Academy, Chernovtsy, Ukraine; e-mail: chornous@chv.ukrpack.net.
2
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine; e-mail:
hetfos@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1483-1486, October,
2004. Original article submitted May 15, 2001.
0009-3122/04/4010-1279©2004 Springer Science+Business Media, Inc.
1279

The acids 2a-e are colorless or light-yellow crystalline substances, the structure of which agrees with the
1
results from elemental analysis and the IR and H NMR spectra (Tables 1 and 2). The IR spectra of the solid
samples contain absorption bands of the C=O bonds of the formyl (1640-1660 cm-1) and carboxyl
(1705-1720 cm-1) groups and also broad absorption bands of OH groups with a hydrogen bond (2900-3200 cm-1),
and this confirms their dimeric nature [5]. In the 1H NMR spectra the carboxyl group has hardly any effect on the
chemical shifts of the 5-CH= proton of the pyrazole ring and leads to slight upfield shifts of the signals for the
aldehydic protons (by 0.09-0.22 ppm) and to more pronounced shifts of the signals for the protons of the CH2
groups (by 0.25-0.45 ppm).
Published data [6, 7] make it possible to regard 3-heterylpropionic acids and their derivatives as subjects
with potential biological activity. We attempted the synthesis of 3-(1-pyrazolyl)propionamides, the most suitable
approach to which seemed to be through the respective acid chlorides. However, it was found that the reaction of
acids of type 2 with thionyl chloride takes place ambiguously, and as a result it is not possible to isolate products
with individual structures. For this reason direct acylation of the amines with the acids 2a-e in the presence of
dicyclohexylcarbodiimide (DCC) was used. This made it possible to obtain the amides 3a-e with yields of 51-
83% (Tables 1 and 2).
EXPERIMENTAL
1
The IR spectra were recorded on a UR-20 instrument in tablets with potassium bromide. The H NMR
spectra were obtained on a Varian Gemini instrument (300 MHz) in DMSO-d6.
3-(3-Aryl-4-formyl-1-pyrazolyl)propionic Acids (2a-e). To 3-aryl-1-(2-cyanoethyl)-4-formylpyrazole
1a-e (50 mmol) we added concentrated hydrochloric acid (20 ml). The mixture was heated to boiling and left at
room temperature for 12 h. We then added water (50 ml). The precipitate was filtered off, dried, and crystallized
from a 1:5 mixture of acetic acid and water.
TABLE 1. The Characteristics of the Synthesized Compounds 2a-e and 3a-g
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
2а
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
C13H12N2O3
63.67
63.93
59.33
59.54
55.77
56.01
48.13
48.30
60.93
61.31
71.60
71.87
65.17
65.39
61.51
61.62
65.03
65.26
57.90
58.22
53.76
54.13
68.33
68.76
4.78
4.92
4.08
4.20
4.20
3.95
3.24
3.41
4.85
5.11
5.28
5.20
4.71
4.90
5.83
5.48
4.07
4.20
4.19
4.36
3.41
3.75
5.30
5.44
11.31
11.48
10.31
10.69
9.83
10.05
8.31
8.67
10.07
10.21
14.36
14.58
11.18
11.44
12.58
12.68
13.60
13.84
9.93
10.19
13.82
14.03
11.80
12.03
121-122
144-145
140-141
124-125
125-126
169-170
137-138
119-120
196-197
185-186
140-141
118-119
82
87
91
93
78
58
76
51
78
58
64
67
C13H11FN2O3
C13H11ClN2O3
C13H11BrN2O3
C14H14N2O4
C23H20N4O2
C20H18FN3O3
C17H18FN3O3
C22H17ClN4O2
C20H18BrN3O2
C18H15BrN4O2
C20H19N3O3
3g
1280

TABLE 2. The Spectral Characteristics of Compounds 2a-e and 3a-g
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
Ar, R2
Com-
pound
α-CH2
(2H, t,
J = 7.5)
CH=O
(1H, s)
5-CH=
(1H, s)
COOH
(1H, br. s)
N–H
(1H, s)
β-CH2 (2H, t,
C=O
O–H
N–H
CH3
J = 7.5)
arom.
(3H, s)
2a
2b
2c
1645, 1715
1650, 1710
1640, 1720
2950, 3200
2900, 3180
2900, 3150
9.86
9.84
9.85
8.47
8.51
8.52
7.40-7.44 (3H, m); 7.78-7.81 (2H, m)
7.19-7.23 (2H, m); 7.86-7.89 (2H, m)
4.42
4.42
4.42
2.88
2.89
2.88
12.39
12.44
12.40
7.44 (2H, d, J = 8.7);
7.87 (2H, d, J = 8.7)
2d
2e
1655, 1715
1660, 1705
2950, 3200
2900, 3130
9.85
9.82
8.52
8.44
7.61 (2H, d, J = 8.5);
7.79 (2H, d, J = 8.5)
4.42
4.40
2.88
2.87
12.41
12.38
7.77 (2H, d, J = 8.6);
6.95 (2H, d, J = 8.6)
3.84
3a
3b
1645, 1660
1650, 1655
3360
3320
9.88
9.84
8.53
8.55
8.18 (1H, d, J = 8.8); 7.23-7.82 (9H, m)
2.64
3.71
4.60
4.51
3.15
2.96
10.07
9.91
6.88 (2H, d, J = 8.6); 7.28-7.30 (2H, m);
7.44 (2H, d, J = 8.6); 7.85-7.88 (2H, m)
3c*
1650, 1665
1650, 1660
9.86
9.85
8.56
8.57
7.28-7.30 (2H, m); 7.88-7.91 (2H, m)
4.54
4.59
3.01
3.10
3d
3290
3350
3260
7.34 (1H, dd, Jo = 8.6, Jm = 2.9);
7.46 (2H, d, J = 8.7); 7.69-7.93 (5H, m);
8.28 (1H, d, J = 8.6);
10.12
9.88
8.84 (1H, d, J = 8.6)
3e
3f
1660, 1675
1680, 1700
9.84
9.86
8.52
8.53
7.05 (2H, d, J = 8.6);
7.43 (2H, d, J = 8.6);
7.57 (2H, d, J = 8.5);
7.82 (2H, d, J = 8.5)
2.32
4.51
4.55
2.95
3.04
7.25-7.27 (1Hpyr, m);
10.23
7.58 (2H, d, J = 8.5);
7.82 (2H, d, J = 8.5);
8.03 (1Hpyr, d, J = 8.6);
8.21 (1Hpyr, d, J = 8.6); 8.67 (1Hpyr, s)
3g
1660, 1670
3250
9.83
8.46
6.96 (2H, d, J = 8.6); 7.24-7.27 (3H, m);
7.57-7.59 (2H, m); 7.75 (2H, d, J = 8.6)
3.81
4.51
2.99
10.01
_______
* The multiplet signals of the protons of the morpholine ring are at 3.29-3.44 (4H) and 3.52-3.57 ppm (4H).

3-(3-Aryl-4-formyl-1-pyrazolyl)propionamides (3a-g). To a solution of the acid 2a-e (3 mmol) in THF
(15 ml) we added the respective amine (3 mmol) and DCC (0.61 g, 3 mmol). The mixture was stirred at room
temperature for 12 h and then at 50°C for 1 h. After cooling the precipitated dicyclohexylurea was filtered off
and washed with THF (2 × 10 ml). The filtrate was evaporated, diethyl ether (20 ml) was added to the residue,
and the mixture was left for 6 h. The precipitate was filtered off, dried, and crystallized from ethanol.
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