Synthesis of derivatives of 3,5-dioxopyrazolidine

Article abstract of DOI:10.1007/s10593-005-0125-4

The reaction of monohydrazides of 2-R-4-methylcyclohex-4-ene-1,1-dicarboxylic acids with ethoxymethylenemalonic acid diethyl ester leads to N-(2,2-diethoxycarbonylethylenyl)hydrazides of 2-R-4-methylcyclohex-4-ene-1,1-dicarboxylic acids, which are acylate

Full text of DOI:10.1007/s10593-005-0125-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 2, 2005
SYNTHESIS OF DERIVATIVES
OF 3,5-DIOXOPYRAZOLIDINE
D. Zicane, I. Ravina, Z. Tetere, and M. Petrova
The reaction of monohydrazides of 2-R-4-methylcyclohex-4-ene-1,1-dicarboxylic acids with
ethoxymethylenemalonic acid diethyl ester leads to N-(2,2-diethoxycarbonylethylenyl)hydrazides of
2-R-4-methylcyclohex-4-ene-1,1-dicarboxylic acids, which are acylated by the anhydrides of
trifluoroacetic and acetic acids with the formation of derivatives of 3,5-dioxopyrazolidine and
5-oxopyrazoline respectively.
Keywords: hydrazides of cyclohexenedicarboxylic acids, 3,5-dioxopyrazolidines, diethyl ester of
ethoxymethylenemalonic acid, 5-oxopyrazolines.
We established previously [1] that the interaction of monohydrazides of 2-R-4-methylcyclohex-4-ene-
1,1-dicarboxylic acids with acid anhydrides leads to the formation of 4,4-spiro-substituted 3,5-dioxo-
pyrazolidines.
The present work is devoted to the study of the possibility of synthesizing derivatives of
3,5-dioxopyrazolidine under analogous conditions from N-substituted monohydrazides. To obtain the latter the
reaction of hydrazides 1a-f with the diethyl ester of ethoxymethylenemalonic acid (2) was carried out. As in the
condensation of ester 2 with arylhydrazines, the reaction of compound 2 with hydrazines 1a-f occurs exclusively
at the enolic ethoxy group of diethyl ethoxymethylenemalonate
2
with the formation of
N-(2,2-diethoxycarbonylethylenyl)hydrazides of 2-R-4-methylcyclohex-4-ene-1,1-dicarboxylic acids 3a-f.
R
R
CONHNH2
COOH
CO–NH–NH–CH=C(CO2Et)2
COOH
EtO–CH=C(CO2Et)2
+
2
Me
Me
1a–f
3a–f
(CF CO)
2O
Ac2O
O
3
OAc
O
R
R
R
N
N
Ac
NH
N
N
CH=C(CO2Et)2
N
CH=C(CO2Et)2
Me
Me
CH=C(CO2Et)2
O
O
Me
O
5a–f
4a–f
B
A
1, 3-5 a R = H, b R = Ph, c R = 4-FC6H4, d R = 4-ClC6H4, e R = 4-BrC6H4, f R = 4-O2NC6H4
__________________________________________________________________________________________
Riga Technical University, Riga LV 1048, Latvia; e-mail: daina_zi@ktf.rtu.lv, marina@osi.lv.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 216-220, February, 2005. Original article
submitted January 20, 2003.
0009-3122/05/4102-0187©2005 Springer Science+Business Media, Inc.
187

TABLE 1. Characteristics of the Synthesized Compounds 3-5
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
Hal
3а
3b
3c
3d
3e
3f
С17Н24N2O7
55.48
55.43
62.05
62.14
59.83
59.76
57.46
57.68
52.71
52.78
56.46
56.44
58.97
58.27
64.55
64.77
62.28
62.16
60.06
59.94
54.72
54.66
58.42
58.59
58.13
58.15
63.82
64.08
61.83
61.72
59.95
59.69
6.25
6.57
6.29
6.36
6.02
5.89
5.74
5.68
5.06
5.20
5.54
5.56
6.32
6.33
5.58
6.14
5.80
5.67
5.35
5.47
4.89
4.99
5.62
5.35
6.25
6.16
5.92
6.04
5.61
5.59
5.38
5.41
7.52
7.60
6.18
6.30
6.12
6.06
5.58
5.85
5.50
5.35
8.32
8.58
7.87
7.99
6.76
6.57
6.34
6.30
6.18
6.08
5.70
5.54
8.93
8.91
7.25
7.14
6.13
5.98
5.83
5.76
5.36
5.57
162-164
168-169
174-176
132-134
137-139
184-186
153-154
131-132
114-116
138-140
140-142
124-125
132-133
102-103
134-136
142-143
132-134
183-185
91.4
78.9
75.4
95.1
97.9
80.6
62.9
65.1
68.4
78.9
78.5
73.7
64.1
61.7
81.1
70.0
71.8
85.7
С23Н28N2O7
С23Н27FN2O7
С23Н27ClN2O7
С23Н27BrN2O7
С23Н27N3O9
С17Н22N2O6
С23Н26N2O6
С23Н25FN2O6
С23Н25ClN2O6
С23Н25BrN2O6
С23Н25N3O8
С19Н24N2O7
С25Н28N2O7
С25Н27FN2O7
С25Н27ClN2O7
С25Н27BrN2O7
С25Н27N3O9
4.14
4.11
7.35
7.40
15.53
15.27
4a
4b
4c
4d
4e
4f
4.08
4.27
7.71
7.70
15.99
15.81
5a
5b
5c
5d
5e
5f
3.90
3.91
7.12
7.05
14.63
14.60
54.72
54.85
58.52
58.48
4.91
4.97
5.35
5.30
5.15
5.12
8.21
8.18
On brief boiling of N-substituted hydrazides 3a-f with trifluoroacetic anhydride diethyl (8-methyl-1,4-
dioxo-6-R-2,3-diazaspiro[4,5]dec-8-en-2-yl)malonates 4a-f are formed. Their structures were established on the
1
1
basis of H NMR spectra and their composition was confirmed by data of elemental analysis. In the H NMR
spectra of compounds 4a-f only one broadened signal was observed at low field for the NH proton at
9.02-10.07 ppm. The characteristic absorption of the trans-fixed fragment =CH–NH– as two doublets
(δ=CH 7.49-7.98, δNH 9.98-10.23 ppm) and the broadened low-field signal of the carboxyl group protons, recorded
in the 1H NMR spectra of compounds 3a-f, were absent.
Reaction of hydrazides 3a-f with acetic anhydride occurs on boiling the initial products for 1 h and
leads to the formation of analogous cyclic but already acetylated products. The presence in the molecule of
3,5-dioxopyrazolidine of two nucleophilic centers affords the possibility of forming products of both
O-acylation (A) and also N-acylation (B). It is not possible to form an opinion on the site of acylation from data
1
of H NMR spectra and elemental analysis. The choice in favor of the O-acyl product was made by us on the
basis of the results of [1] and on the data of IR spectra, in which high frequency absorption bands were observed
for the ester carbonyl of an acetoxy group at 1700-1716 cm-1 and there was no absorption for amide carbonyl
and NH groups.
188

TABLE 2. Spectral Characteristics of the Synthesized Compounds
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (SSCC, J, Hz)*
C=O
2
NH
3
1
4
3a
1740, 1700,
1680, 1640
3315-3215
3300-3200
3330-3220
3328-3220
3350-3220
1.21 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3);
1.66 (3H, s, CH3); 1.97-2.20 (4H, m, 2CH2); 2.58 (2H, m,
2CH); 4.21 (4H, m, 2CH2); 5.42 (1H, m, =CH–); 7.98 (1H,
d, J = 12.5, =CH–); 9.48 (1H, br. s, NH); 10.16 (1H, d,
J = 12.5, NH); 11.20 (1H, br. s, CООH)
3b
3с
3d
3e
1748, 1700,
1690, 1650
1.22 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3); 1.67 (3H,
s, CH3); 2.28-2.89 (4H, m, 2CH2); 3.61 (1H, m, CH);
4.07 (4H, q, J = 7, 2CH2); 5.44 (1H, m, =CH–);
7.16 (5H, m, Ar); 7.69 (1H, d, J = 13, =CH); 9.13 (1H, br. s,
NH); 9.29 (1H, br. s, CООH); 9.93 (1Н, d, J = 13, NH)
1742, 1702,
1675, 1617
1.22 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3); 1.71 (3H,
s, CH3); 2.26-2.82 (4H, m, 2CH2); 2.65 (1H, m, CH);
4.13 (4H, q, J = 7, 2CH2); 5.49 (1H, m, =CH–); 6.78-7.24
(4H, m, Ar); 7.73 (1H, d, J = 13, =CH); 9.29 (1H, br. s,
NH); 9.93 (1Н, d, J = 13, NH); 10.31 (1H, br. s, CООH)
1738, 1700,
1670, 1615
1.23 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3); 1.69 (1H,
s, CH3); 2.19-2.93 (4H, m, 2CH2); 3.63 (1H, m, CH);
4.15 (4H, q, J = 7, 2CH2); 5.51 (1H, m, =CH); 7.26 (4H, m,
Ar); 7.76 (1H, d, J = 14, =CH–); 9.15 (1H, br. s, NH);
9.87 (1Н, d, J = 14, NH); 9.92 (1H, br. s, CООH)
1734, 1702,
1670, 1620
1.21 (3H, t, J = 7, CH3); 1.23 (3H, t, J = 7, CH3); 1.62 (3H,
s, CH3); 1.84-2.91 (4H, m, 2CH2); 3.78 (1H, m, CH);
4.12 (4H, q, J = 7, 2CH2); 5.49 (1H, m, =CH); 7.16 (2H, m,
J = 8, Ar); 7.44 (2H, m, J = 8, Ar); 7.69 (1H, d, J = 14,
=CH–); 10.29 (1Н, d, J = 14, NH); 11.10 (1H, br. s, NH);
11.50 (1H, br. s, CООH)
3f
1730, 1715,
1680, 1615
3400-3310
1.21 (3H, t, J = 7, CH3); 1.23 (3H, t, J = 7, CH3); 1.71 (3H,
s, CH3); 1.92-2.93 (4H, m, 2CH2); 4.05 (1H, m, CH);
4.13 (4H, q, J = 7, 2CH2); 5.59 (1H, m, CH); 7.49 (2H, m,
J = 8, Ar); 7.69 (1H, d, J = 13, =CH–); 8.15 (2H, m, J = 8,
Ar); 10.25 (1Н, d, J = 13, NH); 10.96 (1H, br. s, NH);
11.10 (1H, br. s, CООH)
4a
1740, 1720,
1680, 1610
3100
1.29 (3H, t, J = 7, CH3); 1.32 (3H, t, J = 7, CH3); 1.69 (3H,
s, CH3); 1.89-2.33 (6H, m, 3CH2); 4.24 (2H, q, J = 7, CH2);
4.31 (2H, q, J = 7, CH2); 5.38 (1H, m, =CH–); 8.08 (1H, s,
=CH–); 10.07 (1H, br. s, NH)
4b
1745, 1730,
1680, 1610
3220
3210
1.21 (6H, m, 2CH3); 1.71 (3H, s, CH3); 1.92-3.38 (5H, m,
2CH2, СН); 4.26 (4H, m, 2CH2); 5.43 (1H, m, CH); 7.16
(5H, m, C6H5); 7.96 (1H, s, =СН–); 9.78 (1Н, br. s, NH)
1.25 (3H, t, J = 7, CH3); 1.28 (3H, t, J = 7, CH3);
1.76 (3H, s, CH3); 2.02–2.99 (4H, m, 2CH2);
3.33 (1Н, m, СН); 4.18 (4H, q, J = 7, 2CH2);
5.38 (1H, m, =CH–); 6.89-7.11 (4H, m, Ar);
7.96 (1H, s, =CH–); 9.60 (1H, br. s, NH)
4с
1740, 1720,
1680, 1610
4d
4e
4f
1740, 1725,
1685, 1620
3230
3210
3200
1.29 (3H, t, J = 7, CH3); 1.31 (3H, t, J = 7, CH3); 1.82 (3H,
s, CH3); 2.09-3.39 (5H, m, CH); 3.39 (5Н, m, 2СН2, CH);
4.21 (4H, q, J = 7, 2CH2); 5.42 (1H, m, =CH–); 7.05-7.21
(4H, m, Ar); 9.02 (1H, s, =CH–); 9.02 (1H, br. s, NH)
1745, 1720,
1682, 1615
1.22 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3); 1.73 (3H,
s, CH3); 1.97–3.01 (4H, m, 2CH2); 3.36 (1Н, m, CH);
4.19 (4H, q, J = 7, 2CH2); 5.39 (1H, m, =CH–); 7.05-7.42
(4H, m, Ar); 8.02 (1H, s, =CH–); 9.36 (1H, br. s, NH)
1740, 1716,
1680, 1610
1.25 (6H, m, 2CH3); 1.78 (3H, s, CH3); 2.09-3.09 (4H, m,
2CH2); 3.53 (1Н, m, CH); 4.21 (4H, m, 2CH2);
5.49 (1H, m, CH); 7.31 (2H, m, Ar);
8.11 (3H, m, Ar, =CH–); 9.97 (1H, br. s, NH)
189

TABLE 2 (continued)
1
2
3
4
5a
1760, 1732,
1700, 1630
1.22 (6H, t, J = 7, 2CH3); 1.66 (3H, s, CH3); 1.86-2.38 (6H,
m, 3CH2); 2.53 (3Н, s, CH3); 4.11 (4H, q, J = 7, 2CH2);
5.28 (1H, m, =CH–); 7.44 (1H, s, =CH–)
5b
5c
1770, 1745,
1715, 1645
1.27 (6H, t, J = 7, CH3); 1.29 (3H, t, J = 7, CH3); 1.76 (3Н,
s, CH3); 2.04 (3Н, s, CH3); 2.11-3.01 (4H, m, 2CH2);
3.22 (1Н, m, CH); 4.22 (2H, q, J = 7, CH2); 4.25 (2H, q,
J = 7, CH2); 5.38 (1H, m, =CH–); 7.21 (1H, s, =CH–);
7.25 (5Н, m, Ar)
1.22 (3H, t, J = 7, CH3); 1.25 (3H, t, J = 7, CH3); 1.73 (3Н,
s, CH3); 2.13 (3Н, s, CH3); 2.07-3.02 (4H, m, 2CH2);
3.24 (1Н, m, CH); 4.18 (2H, q, J = 7, CH2); 4.23 (2H, q,
J = 7, CH2); 5.37 (1H, m, =CH–); 7.04 (4H, m, Ar);
7.07 (1Н, m, =CH–)
1760, 1740,
1716, 1640
5d
5e
5f
1765, 1740,
1715, 1640
1.27 (6H, t, J = 7, CH3); 1.29 (3H, t, J = 7, CH3); 1.73 (3Н,
s, CH3); 2.02-2.89 (4H, m, 2CH2); 2.17 (3Н, s, CH3);
3.22 (1H, m, CH); 4.18 (4H, m, 2CH2); 5.41 (1H, m, =CH–);
7.16 (1H, s, =CH–); 7.21 (4Н, m, Ar)
1.24 (3H, t, J = 7, CH3); 1.27 (3H, t, J = 7, CH3); 1.71 (3Н,
s, CH3); 2.07-2.93 (4H, m, 2CH2); 3.21 (1Н, m, CH);
4.18 (4H, m, 2CH2); 5.28 (1H, m, =CH–); 7.11 (2H, m,
J = 8, Ar); 7.11-7.38 (5H, m, Ar, =CH–)
1760, 1740,
1715, 1640
1765, 1730,
1716, 1640
1.26 (3H, t, J = 7, CH3); 1.28 (3H, t, J = 7, CH3); 1.73 (3Н,
s, CH3); 2,16 (3Н, s, CH3); 2.02-3.07 (4H, m, 2CH2);
3.42 (1Н, m, CH); 4.18 (2H, q, J = 7, CH2); 4.21 (2H, q,
J = 7, CH2); 5.38 (1H, m, =CH–); 7.29 (2H, m, J = 8, Ar);
7.32 (1H, s, =CH); 8.16 (2H, m, J = 8, Ar)
_______
* Compounds 3c,f in DMSO-d6, remainder in CDCl3.
EXPERIMENTAL
1
The H NMR spectra were obtained on a WH 90/DS (90 MHz) instrument, solvents were CDCl3 and
DMSO-d6, internal standard was HMDS (0.055 ppm). The IR spectra were recorded on a Specord 75 instrument
for suspensions in nujol and hexafluorobutadiene. The homogeneity of the compounds obtained was checked by
TLC on Silufol plates in the solvent system chloroform–methanol–acetic acid, 95:5:5.
Monohydrazides 1a-f were synthesized by us previously in [3]. The diethyl ester of
ethoxymethylenemalonic acid (2) was given by BAPEKS.
N-(2,2-Diethoxycarbonylethylenyl)hydrazides of 2-R-4-Methylcyclohex-4-ene-1,1-dicarboxylic
Acids (3a-f). A suspension of hydrazide 1a-f (5 mmol) and an equimolar quantity of diethyl ester 2 in ethanol
(40 ml) was boiled for 1 h. Half of the ethanol was distilled off, water (~10 ml) was added to the residue, and the
mixture left for 10-12 h. The mixture was filtered, and the product recrystallized for analysis from ethanol.
Diethyl
(8-Methyl-1,4-dioxo-6-R-2,3-diazaspiro[4,5]dec-8-en-2-yl)methylenemalonate
(4a-f).
Hydrazide 3a-f (1 mmol) was boiled in trifluoroacetic anhydride (1.5 ml) for 1 h. The trifluoroacetic anhydride
was distilled off, and the residue rubbed with hexane. The mixture was filtered, and the solid recrystallized from
ethanol–water, 1:1.
Diethyl (4-Acetoxy-8-methyl-1-oxo-6-R-2,3-diazaspiro[4,5]deca-3,7-dion-2-yl)methylenemalonate
(5a-f). Hydrazide 3a-f (1 mmol) was boiled in acetic anhydride (1.5 ml) for 1 h. The acetic anhydride was
distilled off, water (~10 ml) was added to the residue, and the mixture stirred for 1 h. The aqueous solution was
decanted, and the solidified oil was recrystallized from ethanol.
190

REFERENCES
1.
D. R. Zicane, Z. F. Tetere, I. A. Rijkure, M. V. Petrova, E. Yu. Gudriniece, and U. O. Kalejs, Khim.
Geterotsikl. Soedin., 903 (2000).
2.
3.
D. Zicane, Z. Tetere, I. Ravina, and M. Petrova, RTU 43. Starptautiska zin. konf., Riga, 59 (2002).
D. R. Zicane, I. T. Ravina, I. A. Rijkure, Z. F. Tetere, E Yu. Gudriniece, and U. O. Kalejs, Zh. Org.
Khim., 36, 521 (2000).
191