Synthesis of 1-acyl-5-amino-4-ethoxycarbonylpyrazoles from monohydrazides of cyclohexenedicarboxylic acids and ethyl ethoxymethylenecyanoacetate

Article abstract of DOI:10.1007/s10593-005-0291-4

Heating monohydrazides of cyclohexenedicarboxylic acids with ethyl ethoxymethylenecyanoacetate at reflux gives the corresponding N-substituted hydrazides. This reaction carried out in pyridine gives 1-acyl-5-amino-4- ethoxycarbonylpyrazoles. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0291-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 9, 2005
SYNTHESIS OF 1-ACYL-5-AMINO-
4-ETHOXYCARBONYLPYRAZOLES FROM
MONOHYDRAZIDES OF CYCLOHEXENEDICARBOXYLIC
ACIDS AND ETHYL ETHOXYMETHYLENECYANOACETATE
D. Zicane, Z. Tetere, I. Ravina, and M. Petrova
Heating monohydrazides of cyclohexenedicarboxylic acids with ethyl ethoxymethylenecyanoacetate at
reflux gives the corresponding N-substituted hydrazides. This reaction carried out in pyridine gives
1-acyl-5-amino-4-ethoxycarbonylpyrazoles.
Keywords: hydrazides, pyrazoles, cyclohexenedicarboxylic acid, ethyl ethoxymethylenecyanoacetate.
Pyrazole derivatives such as antipyrine, phenylbutazone, oxyphenbutazone, and sulfinpyrazole are used
as nonsteroidal analgesics and antipyretics [1-4].
The introduction of acyl and aracyl groups into indomethacin and ketophenylbutazone significantly
enhances their therapeutic activity and lipid solubility [5, 6].
These findings led us to study the synthesis of 1-acyl-5-amino-4-ethoxycarbonylpyrazoles from ethyl
ethoxymethylenecyanoacetate (1) and monohydrazides of 2-(4-R-phenyl)-4-cyclohex-4-ene-1,1-dicarboxylic
acids 2a-e described in our previous work [7].
Similar syntheses have been described in the literature. Despite the presence of three reaction sites in
ester 1, the condensation of this compound with hydrazides occurs exclusively at the ethoxymethylene group.
The prolonged heating of ethyl ester 1 with hydrazides of substituted benzoic acids in methanol at reflux in the
presence of catalytic amounts of glacial acetic acid gave 5-amino-1-aroyl-4-ethoxycarbonylpyrazoles [10, 11].
Brief heating of ester 1 and 4(2)-methoxyhydrazides of benzoic acids at reflux gave the corresponding
hydrazones, which, according to Bagrov [9], are incapable of further cyclization.
We have found that both linear and cyclic products may be formed in the reaction of enol ester 1 with
hydrazides of cyclohexenedicarboxylic acids 2a-e, depending on the reaction conditions. The linear intermediate
can undergo cyclization. Heating enol ester 1 with hydrazides 2a-e in ethanol at reflux for 1 h gives N-
substituted hydrazides 3a-e [12], while heating the reaction components in pyridine at reflux for 1 h leads to
pyrazoles 4a-e (Scheme 1).
The products, 1-acyl-5-amino-4-ethoxycarbonylpyrazoles 4a-e, are stable crystalline compounds.
The reaction of pyrazoles 4a-e with formamide under conditions for the synthesis of
pyrazolopyrimidines [8] leads to amides 5a-e [13], while the alkaline hydrolysis of these compounds according
to Schmidt and Drye [8] gave previously unreported cyclohexenecarboxylic acids 6a-e [14] instead of the
expected pyrazolecarboxylic acids.
__________________________________________________________________________________________
Riga Technical University, LV-1048 Riga, Latvia; e-mail: daina_zi@ktf.rtu.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 9, pp. 1332-1335, September, 2005. Original article submitted February 5,
2004.
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0009-3122/05/4109-1130©2005 Springer Science+Business Media, Inc.

Scheme 1
R
N
C
O
O
+
OEt
OEt
H2N
N
H
H
Me
1
HO2C
2a–e
Py, ∆
EtOH, ∆
R
CO2Et
N
C
O
N
NH2
OEt
O
N
O
R
Py, ∆
HCONH2
Me
H
N
H
Me
N
H
HO2C
3a–e
4a–e
Me
_
OH
R
R
O
H2N
Me
HO2C
5a–e
a R = H; b R = F; c R = Cl; d R = Br; e R = NO2
6a–e
TABLE 1. Characteristics of 1-Acyl-5-amino-4-ethoxycarbonylpyrazoles 4a-e
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
H
N
Hal
4а
4b
4c
4d
4e
C20H23N3O3
68.02
67.97
64.82
64.68
61.85
61.93
55.70
55.56
6.58
6.56
6.00
5.97
5.79
5.72
5.10
5.13
11.72
11.89
11.02
11.31
10.72
10.83
9.84
9.72
95-98
49.4
64.3
58.4
59.4
62.3
C20H22FN3O3
C20H22ClN3O3
C20H22BrN3O3
C20H22N4O5
119-120
142-144
150-151
172-173
9.18
9.14
18.54
18.48
60.40
60.29
5.60
5.57
14.18
14.06
1131

TABLE 2. 1H NMR Spectra of 1-Acyl-5-amino-4-ethoxycarbonylpyrazoles 4a-e
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
4а
4b
4c
4d
4e
1.27 (3H, t, J = 7, СН3); 1.69 (3H, s, СН3); 2.09-2.51 (4Н, m, 2СН2); 3.58 (1Н, m, СН);
3.91 (1Н, m, СН); 4.18 (2Н, m, 2СН2); 5.44 (1Н, m, =СН–); 6.89-7.21 (7Н, m, Ar, NH2);
7.58 (1H, s, =CH–)
1.27 (3H, t, J = 7, СН3); 1.71 (3H, s, СН3); 2.11-2.71 (4Н, m, 2СН2); 3.61 (1Н, m, СН);
3.91 (1Н, m, СН); 4.24 (2Н, q, J =7, СН2); 5.44 (1Н, m, =СН–); 6.69–6.93 (6Н, m, Ar,
NH2); 7.62 (1H, s, =CH–)
1.28 (3H, t, J = 7, СН3); 1.67 (3H, s, СН3); 2.09–2.71 (4Н, m, 2СН2); 3.61 (1Н, m, СН);
3.89 (1Н, m, СН); 4.24 (2Н, q, J = 7, СН2); 5.44 (1Н, m, =СН–); 6.84 (2Н, m, J = 8, Ar);
6.92 (2H, br. s, NH2); 7.08 (2Н, m, J = 8, Ar); 7.62 (1Н, s, =CH–)
1.28 (3H, t, J = 7, СН3); 1.73 (3H, s, СН3); 2.08-2.73 (4Н, m, 2СН2); 3.67 (1Н, m, СН);
3.96 (1Н, m, СН); 4.18 (2Н, q, J = 7, СН2); 5.44 (1Н, m, =СН–); 6.84 (2Н, m, J = 7, Ar);
7.01 (2H, br. s, NH2); 7.27 (2Н, m, J = 7, Ar); 7.64 (1Н, s, =CH–)
1.28 (3H, t, J = 7, СН3); 1.73 (3H, s, СН3); 2.11-2.62 (4Н, m, 2СН2); 3.73 (1Н, m, СН);
4.04 (1Н, m, СН); 4.29 (2Н, q, J = 7, СН2); 5.59 (1Н, m, =СН–); 6.89 (2Н, br. s, NH2);
7.07 (2H, m, J = 8, Ar); 7.62 (1Н, s, =CH–); 8.04 (2H, m, J = 8, Ar)
EXPERIMENTAL
1
The H NMR spectra were taken on a WH-90DS spectrometer at 90 MHz in CDCl3 with HMDS
(δ 0.05 ppm) as the internal standard. The purity of the products was checked by thin-layer chromatography on
Silufol plates using 95:5:3 chloroform–methanol–glacial acetic acid as the eluent.
The physicochemical and spectral data of these products are given in Tables 1 and 2.
A sample of ethyl ethoxymethylenecyanoacetate (1) was provided by BAPEKS.
5-Amino-1-[1-carbonyl-2-(4-R-phenyl)-4-cyclohex-4-ene]-4-ethoxycarbonylpyrazoles
4a-e.
A
solution of hydrazides 2a-e (2 mmol) and an equimolar amount of ethyl ester 1 in pyridine (4 ml) was heated at
reflux for 1 h. Pyridine was distilled off and the residue was recrystallized from ethanol (for 4a and 4c-e) or 2:1
ethanol–water (for 4b).
Pyrazoles 4a-e were synthesized analogously from linear N-substituted hydrazides 3a-e.
Amides of 2-(4-R-Phenyl)-4-cyclohex-4-ene-1-carboxylic Acids 5a-5e. A solution of pyrazole 4a-e
(1 mmol) and formamide (0.6 ml) was heated for 8 h at 190-200°C. The mixture was cooled and 1 N aq. NaOH
(~2 ml) was added. The precipitate was filtered off and recrystallized from 1:1 ethanol–water. The data for these
samples of 5a-e were identical to those of samples previously obtained [13].
2-(4-R-Phenyl)-4-cyclohex-4-ene-carboxylic Acids 6a-e. Samples of pyrazoles 4a-e (1 mmol) were
dissolved upon heating in aq. NaOH (2.5 ml). After 15 min, the mixtures were cooled and an equal volume of
water was added. The mixture was acidified to pH ~5 by adding a 1:1 mixture of concentrated hydrochloric acid
and water. The residue was filtered off and recrystallized from 2:1 methanol–water. The data for these samples
of 6a-e were identical to those obtained in our previous work [14].
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