Synthesis and crystal structure of some 3,5-pyrazolidinediones

Article abstract of DOI:10.1007/s10593-010-0527-9

Syntheses of various derivatives of 3,5-pyrazolidenedione are reported. This includes 4-arylidene (alkylidene or aralkylidene)-3,5-pyrazolidinediones, which on epoxidation gave unreported oxiranes. The syntheses of these derivatives were based on either the Knoevenagel reaction of carbonyl derivatives with 3,4-pyrazolidinedione or cyclization of arylidene (alkylidene) malonic acid hydrazide with glacial acetic acid. 4-Arylazo-3,5-pyrazolidinedione derivatives were also prepared by coupling of aryldiazonium salts with 3,5-pyrazolidinedione or cyclization of arylazomalonic acid hydrazide. Reduction of 4-benzylidene derivatives gave the corresponding benzyl derivatives. The structure of the new products was confirmed by elemental and spectral analyses and X-ray crystallography.

Full text of DOI:10.1007/s10593-010-0527-9

Chemistry of Heterocyclic Compounds, Vol. 46, No. 4, 2010
SYNTHESIS AND CRYSTAL STRUCTURE
OF SOME 3,5-PYRAZOLIDINEDIONES
Saoud A. M. Metwally1*, Maisa I. Abdel Moneim1, Yasser A. Elossely1,
Radwa I. Awad2, Khaled Abou-Hadeed3
Syntheses of various derivatives of 3,5-pyrazolidenedione are reported. This includes 4-arylidene (alkylidene
or aralkylidene)-3,5-pyrazolidinediones, which on epoxidation gave unreported oxiranes. The syntheses of
these derivatives were based on either the Knoevenagel reaction of carbonyl derivatives with
3,4-pyrazolidinedione or cyclization of arylidene (alkylidene) malonic acid hydrazide with glacial acetic
acid. 4-Arylazo-3,5-pyrazolidinedione derivatives were also prepared by coupling of aryldiazonium salts
with 3,5-pyrazolidinedione or cyclization of arylazomalonic acid hydrazide. Reduction of 4-benzylidene
derivatives gave the corresponding benzyl derivatives. The structure of the new products was confirmed by
elemental and spectral analyses and X-ray crystallography.
Keywords: 3,5-pyrazolidinediones, X-ray crystallography.
Historically, dyes and pharmaceuticals derived from pyrazolinones were among the first successful
commercial synthetic organic chemicals in which interest has continued actively until the present day. Research
in this field has culminated in the discovery of the useful anti-inflammatory properties of 4-n-butyl-
1,2-diphenyl-3,5-pyrazolidinedione (phenylbutazone) [1]. In spite of the problems encountered in the
undesirable side reactions, principally agranulocytosis produced by these drugs [2-7], interest in them has never
abated and one feels confident in predicting the discovery of additional useful and improved drugs in this class
of compounds [8-10]. The development of new and improved dyes based on pyrazolinone structures has
likewise led to modern developments of no inconsiderable magnitude. The use of tetrazine [11-14] as an
approved color for foodstuffs is of significance. The synthesis of pyrazolinedione dyes for use as magenta
couplers and sensitizers in color photography has been suggested [15, 16]. Metal chelate pyrazolidinone dye
structures have caused a renewed interest in the use of these dyes in analytical procedures [17-19]. Recently 3,5-
pyrazolidinediones have found extensive applications in veterinary medicine [20-34].
_______
* To whom correspondence should be addressed, e-mail: Saoudmetwally@hotmail.com.
1Chemistry Department, Assiut University, Egypt.
2Forensic Medicine Laboratories, Assiut, Egypt.
3Institute of Organic Chemistry, University of Zurich, Switzerland.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 538-550, April 2010. Original
article received January 22, 2009. After revision rewind October 31, 2009.
426
0009-3122/10/4604-0426©2010 Springer Science+Business Media, Inc.

The aim of this work is the synthesis of 3,5-pyrazolidenedione derivatives 6 starting from the
unsubstituted 3,5-pyrazolidinedione (5) or malonic acid hydrazide derivatives 8 and 15. As an important starting
material in this work, 3,5-pyrazolidinedione (5) was prepared according to [35] via cyclization of
ethoxycarbonylacetohydrazide (3) [36] using sodium methoxide. Condensation of compound 5 with aliphatic or
aromatic carbonyl derivatives gave the corresponding 4-alkylidene(arylidene)- or (aralkylidene)-3,5-pyrazolidine-
diones 6.
O
O
C
C
OEt
OEt
C
C
NHNH2
OEt
CONHNH2
CONHNH2
4
H2NNH2
+
+
2
O
O
1
3
MeONa
–15oC
R
R1
+
H
–
O
O
O
C
Na
RCOR1
AcOH
HN
HN
HN
O
N
O
N
H
O
N
H
H
5
6a–g
6 a R = R1 = Me; bf R = H, b R1 = p-BrC6H4, c R1 = p-ClC6H4, d R1 = p-OHC6H4,
e R1 = p-Me2NC6H3, f R1 = p-MeC6H4, g R + R1 = 4-(indoxyl-3-yl)
On the other hand, cyclization of alkylidene- or arylidenemalonic acid hydrazides 8 using glacial acetic
acid yielded 1-acetyl-4-alkylidene(arylidene)-3,5-pyrazolidinediones 9.
O
R
C
C
O
OEt
OEt
R
C
1
O
+
C
C
R1
R1
7
H2NNH2
O
R
C
R 1
O
AcOH
C
C
O
NHNH2
NHNH2
R
C
C
HN
O
N
R1
COMe
8
9
9 a R = H, R1 = o-O2NC6H4; b R = R1 = isopropylidine;
ch R = H, c R1 = p-MeC6H4, d R1 = p-Me2NC6H3, e R1 = p-ClC6H4,
f R1 = p-O2NC6H4, g R1 = m-O2NC6H4, h R1 = p-HOC6H4
427

Fig. 1. The chemical structure of compounds 6a (a), 6e (b), and 10 (c)
428

The structure of 4-substituted 3,5-pyrazolidinediones 6 and 1-acetyl derivatives 9 [37] was determined
using elemental analysis and spectroscopic methods.
Epoxidation of some 4-alkylidene or arylidene-3,5-pyrazolidinediones 6a,e using alkaline hydrogen
peroxide in ether [38] yielded the unreported oxirane derivatives 10 and 11.
Me
O
O
NH
O
O
Me
HN
O
O
N
HN
H
O
N
H
10
11
The chemical structure of compounds 6a,e and 10 has been solved and refined successfully using X-ray
crystallography (Fig. 1a−c). Both ring N-atoms showed a slight pyramidalization in compound 6a and significant
pyramidalization in compounds 6e and 10 and particularly at N(2), rather than the usual planar arrangement
common in amides. This is probably due to preferential delocalization of the C=O bonds with the C(4)=C(6)
bond. The phenyl ring and C(10)−N(13) bonds showed a slight trend towards a quinoline type double bond
localization, but the effect is very small. The X-ray structure of compound 6a indicated that one amide group
forms an intermolecular hydrogen bond with the O-atom of the same amide group of an adjacent molecule,
thereby linking pairs of molecules into centrosymmetric dimers. The other amide group forms bifurcated
intermolecular hydrogen bonds. The combination of these interactions creates a two-dimensional network. See
Table 1 for full details.
A series of 4-arylazo-3,5-pyrazolidinediones 13 was prepared either by coupling aryl diazonium salts 12
with compound 5 or cyclization of arylazomalonic acid hydrazide 15 using acetic acid to give 1-acetyl-
4-arylazo-3,5-pyrazolidinedione derivatives 16.
O
N
NAr
NaNO2
HCl, 5°C
1
+
ArN
5
ArNH2
N
–
HN
+
AcO Na
12
O
N
H
13a–d
O
N
NAr
N2H4
AcOH
ArN NCH
(COOEt)2
HN
(CONHNH )
2 2
ArN NCH
O
N
14a,b
15a,b
COMe
16a,b
13 a Ar = Ph, b Ar = p-MeOC6H4; 13c, 14a16a Ar = O2NC6H4;
13d,14b16b Ar = o-ClC6H4
The structure of 4-arylazo-3,5-pyrazolidinedione 13 or its 1-acetyl derivatives 16 was confirmed using
elemental analysis and spectroscopic methods.
The exocyclic double bond at position 4 of compounds 6e and 9f was smoothly reduced to the
corresponding single bond using sodium borohydride in methanol [39], yielding the corresponding 4-benzyl
derivatives 17 and 18, respectively.
429

O
NMe2
CH2
O
O
NO2
CH2
O
HN
HN
N
N
H
17
Ac
18
TABLE 1. Crystallographic Data
6a
6e
10
Crystallized from
Empirical formula
Formula weight, gmol–1
Crystal color, habit
Crystal dimensions, mm
Temperature, K
Crystal system
MeOH
DMF/H2O
C12H13N3O2
231.25
MeOH
C6H8N2O2
140.14
Yellow, plate
0.070.200.25
160(1)
C6H8N2O3
156.14
Colorless, plate
0.070.220.25
160(1)
Red, prism
0.120.200.20
160(1)
Triclinic
P1
Monoclinic
P21/c
Orthorhombic
Pbca
Space group
Z
4
2
8
Reflections for cell determination
2range for cell determination, deg
Unit cell parameters
a, Å
1211
2923
4-60
2299
4-50
4-60
7.5852(3)
6.8324(5)
12.5924(7)
90
6.0986(4)
7.9152(5)
11.4088(6)
100.815(4)
94.040(4)
102.145(3)
525.36(6)
244
11.2797(3)
8.5218(2)
14.3066(3)
90
b, Å
c, Å
α, deg
β, deg
104.773(4)
90
90
γ, deg
V, Å3
90
631.03(6)
296
1375.20(6)
656
F(000)
Dx, gcm–3
1.475
1.462
1.508
μ(MoKα), mm–1
Scan type
0.113
0.103
0.122
 and 
50
 and 
60
 and 
60
2max, deg
Total reflections measured
Symmetry-independent reflections
Rint
9933
13 664
3059
23 769
2002
1111
0.063
0.047
0.056
Reflections with I<2 (I )
Reflections used in refinement
Parameters refined
R(F) [I<2 (I ) reflections]
wR(F2) (all independent reflections)
Weighting parameters [a;b]*
GOOF
932
2232
1613
1110
3059
2002
101
164
111
0.0430
0.1144
0.062; 0.164
0.0549
0.1547
0.0818; 0.1463
0.0403
0.1078
0.0505; 0.293
1.064
1.067
—
1.028
—
Secondary extinction coefficient
Final max /
0.015(3)
0.001
0.001
0.001
 (max, min), e Å–3
0.16; -0.23
0.33; -0.33
0.29; -0.23
_______
* w–1= 2(Fo ) + (aP)2 + bP, where P = (Fo + 2Fc2)/3.
2
2
EXPERIMENTAL
1
IR spectra were determined on a Shimadzu 480 IR spectrophotometer using the KBr pellet technique. H
and 13C NMR spectra were recorded on a JEOL LA 400 NMR spectrometer (400 and 100 MHz respectively),
430

solvent DMSO-d6, internal standard TMS. The mass spectra were obtained on a JEOL route-600 H spectrometer
using the direct inlet technique at 70 eV. All melting points were determined on an electric melting point
apparatus (Gallenkamp) and are uncorrected. Elemental analyses were carried out by the microanalytical unit at
Chemistry Department, Assiut University, using an Elementar Vario EI elemental analyzer.
Ethoxycarbonylacetohydrazide (3). The following is an improved preparation method [36]. Hydrazine
hydrate (6.0 g, 0.187 mol ) was added at room temperature to a solution of diethyl malonate (50 g, 0.312 mol) in
ethanol (20 ml). The mixture was stored overnight, and malonohydrazide (4) (3.9 g) was separated by filtration,
mp 151-153°C (154°C [40]). Evaporation of the filtrate left a partly crystalline residue, which was washed with
ether to remove the unchanged ester. The solid ethoxycarbonylacetohydrazide was recrystallized twice from
ethanol. Yield 7.5 g; mp 68-69°C (70°C [36]). The experiment was repeated twice with the recovered diethyl
malonate; each time 0.3 mol of hydrazine hydrate was used. Total yield 15.5 g (34%) based on the original 50 g
1
of diethyl malonate (8% [41]). IR spectrum, , cm–1: 3300, 3040 (NH2, NH), 1725, 1645 (C=O). H NMR
spectrum, , ppm (J, Hz): 1.16 (3H, t, J = 7.1, CH3); 3.13 (2H, s, CH2); 4.05 (2H, q, J = 7.1, CH2); 9.10 (1H, s,
NH). 13C NMR, , ppm: 14.05 (CH3); 38.80 (CH2); 164 (C=O). Mass spectrum, m/z (Irel, %): 146 [M]+ (42), 115
(14), 101 (65), 100 (72), 87 (32), 69 (18), 60 (14), 59 (20), 58 (20), 32 (100). Found, %: C 41.18; H 6.84;
N 19.21. C5H10N2O3. Calculated, %: C 41.09; H 6.90; N 19.17.
Malonohydrazide (4). Colorless flakes from ethanol. Yield 3.9 g (4.7%); mp 151-153°C (154°C [40]).
1
IR spectrum, , cm–1: 3295–3100 (NH2, NH), 1640 (C=O). H NMR spectrum, , ppm (J, Hz): 3.41 (2H, s,
CH2); 9.06 (1H, s, NH); 10.32 (2H, s, NH). Mass spectrum, m/z (Irel, %): 132 [M]+ (35), 131 (25), 100 (84), 99
(74), 74 (18), 69 (58), 59 (72), 45 (17), 44 (94), 43 (88), 42 (70), 33 (68), 32 (100). Found, %: C 27.31; H 6.12;
N 42.32. C3H8N4O2. Calculated, %: C 27.27; H 6.10; N 42.41.
3,5-Pyrazolidinedione (5). A solution of sodium methoxide (0.7 g sodium dissolved in 10 ml dry
methanol) was added dropwise during 4-5 h to a cold solution of ethoxycarbonylacetohydrazide 3 (5 g dissolved in
35 ml dry methanol). The mixture was left in a refrigerator for 24 h, then filtered off, and the filtrate was cooled to -
15°C and neutralized with glacial acetic acid (3.4 ml). The precipitated crystals were collected by filtration, washed
with cold methanol, and dried. Colorless needles from methanol, 2.38 g, 70%; mp 290°C (decomp) (290°C [35]).
1
IR spectrum, , cm–1: 2995, 2720 (broad, NH, OH), 1655 (C=O). H NMR spectrum, , ppm: 3.03 (2H, s, CH2);
10.31 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 40.05 (CH); 169.20 (C=O). Mass spectrum, m/z (Irel, %): 100
[M]+ (100). Found, %: C 35.99; H 3.99; N 27.92. C3H4N2O2. Calculated, %: C 36.01; H 4.03; N 27.99.
Reaction of 3,5-Pyrazolidinedione (5) with Carbonyl Derivatives (General Method). A mixture of
equimolar amounts of compound 5 and the selected carbonyl reagent (aldehyde or ketone) in pure methanol was
refluxed for 30 min. After cooling, the precipitated product was collected and crystallized from the proper
solvent and identified as a 4-alkylidene(arylidene)-3,5-pyrazolidinedione 6.
4-Isopropylidene-3,5-pyrazolidinedione (6a). Yellow plates from methanol. Yield 76%; mp 238-239°C.
1
IR spectrum, , cm–1: 3290 (NH), 1650 (C=O). H NMR spectrum, , ppm: 2.41 (6H, s, CH2); 7.82 (2H, br. s,
13
2NH). C NMR spectrum, , ppm: 22.16 (CH3), 23.19 (CH3), 136.92 (C-6); 160.10 (C-4); 166.92 (C-3); 173.91
(C-5). Mass spectrum, m/z (Irel, %): 140 [M]+ (81), 125 (64), 123 (66), 109 (50), 97 (44), 83 (35), 82 (75), 72 (42),
67 (100). Found, %: C 51.36; H 5.81; N 19.87. C6H8N2O2. Calculated, %: C 51.42; H 5.75; N 19.99.
4-(4'-Bromobenzylidene)-3,5-pyrazolidenedione (6b). Dark-yellow flakes from ethanol. Yield 86%;
1
mp 160°C. IR spectrum, , cm–1: 3210 (NH), 1690 (C=O). H NMR spectrum, , ppm: 7.12-7.82 (4H, m, Ar);
8.61 (1H, s, =CH); 9.90 (2H, s, 2NH). 13C NMR spectrum, , ppm: 115.1, 117.1, 119.3, 124.3, 172.2, 185.1. Mass
spectrum, m/z (Irel, %): 265 [M]+ (58), 239 (42), 237 (38), 210 (90), 208 (100), 182 (32), 181 (36), 103 (55), 102
(52), 101 (28), 90 (31), 89 (63). Found, %: C 44.82; H 2.75; Br 29.63; N 10.43. C10H7BrN2O2. Calculated, %:
C 44.97; H 2.64; Br 29.92; N 10.49.
4-(4'-Chlorobenzylidene)-3,5-pyrazolidinedione (6c). Colorless needles from ethanol. Yield 63%; mp
1
176-177°C. IR spectrum, , cm–1: 3200 (NH); 1680 (C=O). H NMR spectrum, , ppm: 7.53-8.20 (4H, m, Ar);
8.69 (1H, s, =CH); 11.83 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 116, 118, 122.1, 126.3, 132.1, 136.2,
431

138.1, 162.1, 174.4. Mass spectrum, m/z (Irel, %): 222 [M]+ (93), 178 (14), 165 (100), 153 (60), 139 (66), 138
(80), 136 (80). Found, %: C 45.53; H 3.11; Cl 14.78; N 23.52. C9H7ClN4O2. Calculated, %: C 45.30; H 2.96;
Cl 14.86; N 23.48.
4-(4'-Hydroxybenzylidene)-3,5-pyrazolidinedione (6d). Grayish needles from ethanol. Yield 80%; mp
260-261°C. IR spectrum, , cm–1: 3100 (NH), 1650 (C=O). 1H NMR spectrum, , ppm: 7.537.93 (4H, m, Ar);
8.69 (1H, s, =CH); 11.83 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 116, 118, 119, 122.2, 126.1, 130.1,
132.2, 162.1, 174.3. Mass spectrum, m/z (Irel, %): 204 [M]+ (100), 203 (9), 146 (98), 136 (27.4), 120 (8), 119
(18), 118 (100). Found, %: C 58.66; H 4.11; N 13.69. C10H8N2O3. Calculated, %: C 58.82; H 3.95; N 13.72.
4-(4'-N,N-Dimethylaminobenzylidene)-3,5-pyrazolidinedione (6e). Red prisms from DMFH2O, 1:1.
1
Yield 86%; mp 266-267°C. IR spectrum, , cm–1: 3450 (OH or NH), 1690 (C=O). H NMR spectrum, , ppm:
3.06 (6H, s, 2CH3); 6.74-8.10 (4H, m, Ar); 8.53 (1H, s, =CH); 9.22 (2H, br. s, 2NH). 13C NMR spectrum,
, ppm: 39.5 (2CH3), 117.3, 119.2, 132.1, 140.3, 164.2, 171.2. Mass spectrum, m/z (Irel, %): 231 [M]+ (100), 230
(32), 202 (4), 163 (7.3), 147 (5.2), 146 (12), 145 (24), 173 (78). Found, %: C 62.46; H 5.73; N 18.24.
C12H13N3O2. Calculated, %: C 62.33; H 5.67; N 18.17.
4-(4'-Methylbenzylidene)-3,5-pyrazolidinedione (6f). Colorless needles from ethanol. Yield 58%; mp
1
269-270°C. IR spectrum, , cm–1: 3100 (NH), 1655 (C=O). H NMR spectrum, , ppm: 2.52 (3H, s, CH3);
7.41-7.65 (4H, m, Ar); 8.21 (1H, s, CH); 9.72 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 40.0 (CH3); 118.1,
121.1, 132.3, 135.0, 162.3, 174.2 (C=O). Mass spectrum, m/z (Irel, %): 202 [M]+ (100), 187 (50), 174 (32), 146
(21), 113 (46). Found, %: C 65.42; H 5.02; N 13.76. C11H10N2O2. Calculated, %: C 65.34; H 4.98; N 13.85.
4-(Indoxyl-3-yl)-3,5-pyrazolidenedione (6g). Dark-grey needles from methanol. Yield 82%; mp
1
209-210°C. IR spectrum, , cm–1: 3450, 3250 (OH, NH), 1680 (C=O). H NMR spectrum, , ppm: multiplet,
7.35-7.62 (4H, m, Ar); 9.82 (2H, br. s, 3NH). 13C NMR spectrum, , ppm: 118.1, 119.1, 121.3, 129.1, 142.2,
165.1, 172.1. Mass spectrum, m/z (Irel, %): 229 [M]+ (100). Found, %: C 57.72; H 3.21; N 18.45. C11H7N3O3.
Calculated, %: C 57.65; H 3.08; N 18.33.
1-Acetyl-4-(2'-nitrobenzylidene)-3,5-pyrazolidinedione (9a). This derivative was prepared by fusion
of equimolar amounts of o-nitrobenzaldehyde and compound 5 in the presence of a few drops of acetic
anhydride for 5 min. The melt was cooled and triturated with ether. The solid was collected by filteration and
crystallized from ethanol. Yield 86%; mp 181-182°C. IR spectrum, , cm–1: 3200, 3100 (NH), 1640 (C=O).
1H NMR spectrum, , ppm: 2.37 (3H, s, COCH3), 7.92-8.31 (4H, m, Ar); 8.40 (1H, s, CH); 10.21 (1H, s, NH). 13C
NMR spectrum, , ppm: 22.1 (CH3); 123.4, 127.2, 176.1. Mass spectrum, m/z (Irel, %): 233 [M]+ (100), 203 (2), 149
(4), 148 (3), 147 (1). Found, %: C 52.85; H 3.42; N 15.32. C12H9N3O5. Calculated, %: C 52.37; H 3.30; N 15.27.
Synthesis of 1-Acetyl-4-alkylidene(arylidene)-3,5-pyrazolidenediones 9 from Malonohydrazide 4
and Carbonyl Derivatives 9 (General Method). A mixture of equimolar amounts of malonohydrazide 4 and
the proper aldehyde or ketone dissolved in glacial acetic acid was refluxed for 30 min. The precipitated product
on cooling was collected and crystallized from the proper solvent. All products were characterized as 1-acetyl-
4-substituted 3,5-pyrazolidinediones 9 [37].
1-Acetyl-4-isopropylidene-3,5-pyrazolidinedione (9b). Yellow needles from methanol. Yield 75%;
1
mp 252-253°C. IR spectrum, , cm–1: 3200 (NH), 1710, 1680 (C=O). H NMR spectrum, , ppm: 2.38 (6H, s,
2CH3); 2.52 (3H, s, COCH3); 9.21 (1H, s, NH). 13C NMR spectrum, , ppm: 118.2, 165.2, 171.5. Mass
spectrum, m/z (Irel, %): 182 [M]+ (42), 140 (100), 125 (40), 115 (7), 92 (11), 89 (14), 75 (13), 43 (99). Found, %:
C 52.68; H 5.62; N 15.22. C8H10N2O3. Calculated, %: C 52.74; H 5.53; N 15.38.
1-Acetyl-4-(4'-methoxybenzylidene)-3,5-pyrazolidinedione (9c). Colorless needles from methanol.
1
Yield 63%; mp 200-201°C. IR spectrum, , cm–1: 3150 (NH), 1720, 1675 (C=O). H NMR spectrum, , ppm:
2.45 (3H, s, COCH3); 3.15 (3H, s, OCH3); 7.41–7.63 (4H, m, Ar); 8.33 (1H, s, =CH); 9.50 (1H, br. s, NH). 13C
NMR spectrum, , ppm: 24.1 (CH3); 43.0 (COCH3); 116.1, 118.3, 122.2, 126.1, 162.3, 174.4 (C=O). Mass
spectrum, m/z (Irel, %): 260 [M]+ (100), 229 (45), 218 (31), 155 (21). Found, %: C 60.21; H 4.83; N 14.75.
C13H12N2O4. Calculated, %: C 60; H 4.65; N 10.76.
432

1-Acetyl-4-(4'-N,N-dimethylaminobenzylidene)-3,5-pyrazolidinedione (9d). Red needles from
1
DMF–H2O, 1:1. Yield 63%; mp 266–267°C. IR spectrum, , cm–1: 3190 (NH), 1715, 1670 (C=O). H NMR
spectrum, , ppm: 2.51 (3H, s, COCH3); 3.15 (6H, s, NCH3); 7.12 (4H, m, Ar); 7.75 (1H, s, =CH); 8.51 (1H, br.
s, NH). 13C NMR spectrum, , ppm: 39.1, 42.0, 121.2, 122.3, 125.1, 172.0. Mass spectrum, m/z (Irel, %): 273 [M]+
(22), 258 (15), 231 (100), 229 (63), 155 (18). Found, %: C 61.72; H 5.72; N 15.42. C14H15N3O3. Calculated, %:
C 61.53; H 5.53; N 15.38.
1-Acetyl-4-(4'-chlorobenzylidene)-3,5-pyrazolidinedione (9e). Colorless needles from methanol.
1
Yield 61%; mp 160-161°C. IR spectrum, , cm–1: 3120 (NH), 1710, 1680 (C=O). H NMR spectrum, , ppm:
2.52 (3H, s, COCH3); 7.31-7.52 (4H, m, Ar); 8.42 (1H, s, =CH); 9.42 (1H, s, NH). 13C NMR spectrum, , ppm:
21.1, 116.3, 123.1, 124.2, 162.1, 172.0. Mass spectrum, m/z (Irel, %): 264 [M]+ (100), 231 (24), 222 (52), 153
(14). Found, %: C 54.62; H 3.52; Cl 13.32; N 10.66. C12H9ClN2O2. Calculated, %: C 54.46; H 3.43; Cl 13.40;
N 10.58.
1-Acetyl-4-(4'-nitrobenzylidene)-3,5-pyrazolidinedione (9f). Pale-yellow needles from methanol.
1
Yield 62%; mp 210-211°C. IR spectrum, , cm–1: 3210 (NH), 1705, 1670 (C=O), 1550 (NO2). H NMR
spectrum, , ppm: 2.51 (3H, s, COCH3); 7.42–7.81 (4H, m, Ar); 8.32 (1H, s, =CH); 9.22 (1H, s, NH). 13C NMR
spectrum, , ppm: 21.2, 114.1, 115.2, 116.1, 123.1, 165.4, 172.3. Mass spectrum, m/z (Irel, %): 275 [M]+ (100),
259 (15), 233 (72), 229 (13). Found, %: C 52.44; H 3.25; N 15.18. C12H9N3O5. Calculated, %: C 52.37; H 3.30;
N 15.27.
1-Acetyl-4-(3'-nitrobenzylidene)-3,5-pyrazolidinedione (9g). Brown needles from ethanol. Yield
1
68%; mp 206-207°C. IR spectrum, , cm–1: 3120 (NH), 1710, 1680 (C=O), 1555 (NO2). H NMR spectrum, ,
ppm: 2.52 (3H, s, COCH3); 7.32-7.61 (4H, m, Ar); 7.91 (1H, s, =CH); 9.15 (1H, s, NH). 13C NMR spectrum, ,
ppm: 22.3, 120.1, 126.2, 132.1, 165.1, 175.4. Found, %: C 52.47; H 3.44; N 15.33. C12H9N3O5. Calculated, %:
C 52.37; H 3.30; N 15.27.
1-Acetyl-4-(4'-hydroxybenzylidene)-3,5-pyrazolidinedione (9h). Grayish needles from ethanol. Yield
1
86%; mp 250-251°C. IR spectrum, , cm–1: 3600 (OH), 3250 (NH), 1705, 1660 (C=O). H NMR spectrum, ,
ppm: 2.41 (3H, s, COCH3); 6.92-7.77 (4H, m, Ar); 8.72 (1H, s, =CH); 10.63 (1H, s, NH). 13C NMR spectrum, ,
ppm: 25.1, 119.3, 124.0, 169.3, 170.2, 172.1. Mass spectrum, m/z (Irel, %): 246 [M]+ (100).
Epoxidation of 4-alkylidene(arylidene)-3,5-pyrazolidinedione (6) (General Method). A suspension
of the compound 5 derivative (0.01 mol) in hydrogen peroxide (30 volume, 5 ml) and ether (10 ml) was stirred
until the color disappeared. The solid was filtered, washed with cold methanol, and crystallized from the proper
solvent.
2,2-Dimethyl-1-oxa-5,6-diazaspiro[2,4]heptane-4,7-dione (10). Colorless plates from methanol. Yield
1
54%; mp 207-208°C. IR spectrum, , cm–1: 3199 (NH), 1680 (C=O). H NMR spectrum, , ppm: 1.51 (6H, s,
CH3); 13.25 (2H, s, 2NH). 13C NMR spectrum, , ppm: 18.1, 68.5, 58.6, 166.2. Mass spectrum, m/z (Irel, %): 156
[M]+ (30), 116 (75), 70 (11), 69 (25), 59 (16), 58 (13), 45 (100), 44 (34), 43 (82), 42 (43), 41 (58). Found, %:
C 46.22; H 5.22; N 18.1. C6H8N2O3. Calculated, %: C 46.15; H 5.16; N 17.94.
2,3-Dihydro-1H-dispiro[indole-3,2'-oxirane-3',4''-pyrazolidine]-2,3'',5''-trione (11). Yellow needles
from ethanol. Yield 56%; mp 268-270°C. IR spectrum, , cm–1: 3450 (OH), 3250 (NH), 1690 (C=O). 1H NMR
spectrum, , ppm: 6.93-7.57 (4H, m, Ar); 10.22 (2H, s, 2NH). 13C NMR spectrum, , ppm: 65.9, 90.3, 120.3,
124.3, 125.6, 128.2, 129.6, 137.7, 172.7, 174.8. Mass spectrum, m/z (Irel, %): 245 [M]+ (100). Found, %:
C 53.72; H 2.72; N 17.26. C11H7N3O4. Calculated, %: C 53.88; H 2.88; N 17.14.
Synthesis of 4-Arylazo-3,5-pyrazolidinediones 13 (General Method). The primary aromatic amine
derivative (0.01 mol) was diazotized by dissolving in hydrochloric acid (2.5 mol) and the resulting solution was
cooled in an ice-salt bath to -5°C, then the equivalent amount of sodium nitrite (0.01 mol) dissolved in water
(5 ml) was added. The resulting diazonium salt was coupled with compound 5 (0.01 mol) dissolved in methanol
(10 ml) and the mixture was neutralized with sodium acetate. The precipitated azo dye was filtered off, washed
thoroughly with water, dried, and crystallized from the proper solvent.
433

4-Phenylazo-3,5-pyrazolidinedione (13a). Red needles from methanol. Yield 70%; mp 278-279°C. IR
1
spectrum, , cm–1: 3290, 3215 (NH), 1655 (C=O). H NMR spectrum, , ppm: 3.52 (1H, s, CH); 7.44 (5H, m,
13
Ar); 7.97 (2H, br. s, NH). C NMR spectrum, , ppm: 80.6, 122.3, 125.0, 129.1, 170.3. Mass spectrum, m/z (Irel,
%): 204 [M]+ (100), 197 (2), 194 (1.5), 176 (2), 169 (3), 145 (5.3), 127 (37), 107 (4), 105 (9), 93 (34), 92 (35),
78 (11), 77 (67), 64 (18), 65 (46.6). Found, %: C 53.12; H 4.21; N 27.36. C9H8N4O2. Calculated, %: C 52.94;
H 3.95; N 27.44.
4-(4'-Methoxyphenylazo)-3,5-pyrazolidinedione (13b). Dark-red needles from methanol. Yield 43%;
1
mp 230-231°C. IR spectrum, , cm–1: 3450 (OH), 3350 (NH), 1640 (C=O). H NMR spectrum, , ppm: 3.42
(1H, s, CH); 3.73 (3H, s, CH3O); 6.91 (4H, m, Ar); 9.85 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 56.0,
80.6, 114.6, 123.3, 143.2, 159.4, 170.3. Mass spectrum, m/z (Irel, %): 234 [M]+ (75), 197 (2), 175 (3), 149 (2), 147
(3), 123 (21), 122 (100), 121 (14), 108 (14), 107 (9), 95 (13), 60 (44), 45 (68), 43 (79). Found, %: C 51.36;
H 4.25; N 22.82. C10H10N4O3. Calculated, %: C 51.28; H 4.30; N 23.92.
4-(2'-Nitrophenylazo)-3,5-pyrazolidinedione (13c). Red needles from methanol. Yield 80%; mp
309-310°C. IR spectrum, , cm–1: 3400 (OH), 3250 (NH), 1665 (C=O), 1550 (NO2). 1H NMR spectrum, , ppm:
3.41 (1H, s, CH); 6.60 (4H, m, Ar); 9.23 (2H, s, NH). 13C NMR spectrum, , ppm: 80.6, 115.9, 120.1, 123.3,
123.7, 143.8, 170.3. Mass spectrum, m/z (Irel, %): 249 [M]+ (20), 248 (100), 163 (21), 150 (5), 138 (39), 136
(10), 127 (71), 122 (16), 90 (12), 43 (37). Found, %: C 43.42; H 2.95; N 28.23. C9H7N5O4. Calculated, %: C
43.38; H 2.83; N 28.11.
4-(2'-Chlorophenylazo)-3,5-pyrazolidinedione (13d). Dark-red needles from methanol. Yield 84%;
1
mp 280-281°C. IR spectrum, , cm–1: 3100 (NH), 1665 (C=O). H NMR spectrum, , ppm: 3.41 (1H, s, CH);
7.22 (4H, m, Ar); 9.62 (2H, s, 2NH). 13C NMR spectrum, , ppm: 82.4, 115.1, 122.3, 124.1, 125.1, 144.3, 170.4.
Mass spectrum, m/z (Irel, %): 238 [M]+ (100). Found, %: 45.41; H 3.15; Cl 14.75; N 23.53. C9H7ClN4O2.
Calculated, %: C 45.30; H 2.96; Cl 14.86; N 23.48.
Synthesis of Diethyl Arylazomalonate 14 (General Method). The aryl diazonium salts were prepared
by diazotization of the corresponding primary aromatic amines using sodium nitrite and hydrochloric acid. It
was coupled with the equivalent amount of diethyl malonate and the mixture was neutralized using sodium
acetate to give the required azo derivative. The dye was filtered off, washed with water, and dried.
Diethyl 2-Nitrophenylazomalonate (14a). Pale-yellow needles from ethanol. Yield 75%; mp 79-80°C.
1
IR spectrum, , cm–1: 1715 (C=O), 1525 (NO2). H NMR spectrum, , ppm (J, Hz): 1.26 (6H, t, J = 6.7, 2CH3);
3.32 (1H, s, CH); 4.21 (4H, q, J = 6.7, 2CH2); 7.51 (4H, m, Ar). 13C NMR spectrum, , ppm: 22.1, 38.3, 54.0,
119.4, 123.2, 128.1, 171.4. Mass spectrum, m/z (Irel, %): 309 [M]+ (100). Found, %: C 50.52; H 4.72; N 13.65.
C13H15N3O6. Calculated, %: C 50.49; H 4.89; N 13.59.
Diethyl 2-Chlorophenylazomalonate (14b). Yellow needles from ethanol. Yield 73%; mp 60-61°C. IR
1
spectrum, , cm–1: 1710 (C=O). H NMR spectrum, , ppm (J, Hz): 1.26 (6H, t, J = 6.4, 2CH3); 3.32 (1H, s,
CH); 4.25 (4H, q, J = 6.4, 2CH2); 7.62 (4H, m, Ar). 13C NMR spectrum, , ppm: 21.3, 38.1, 53.1, 122.0, 124.4,
130.2, 169.3. Mass spectrum, m/z (Irel, %): 298 [M]+ (43), 297 (69), 254 (11), 225 (35), 223 (79), 153 (18), 128
(21), 127 (61), 126 (60), 125 (100), 113 (15), 111 (38), 99 (56). Found, %: C 52.41; H 5.12; Cl 11.83; N 9.35.
C13H15ClN2O4. Calculated, %: C 52.27; H 5.06; Cl 11.87; N 9.38.
Synthesis of Arylazomalonic Acid Hydrazides (15) (General Method). The arylazo diethyl malonate
(0.01 mol) was dissolved in absolute ethanol (20 ml), the solution was treated with hydrazine hydrate
(0.03 mol), and the mixture was stirred for 2 h. The precipitated product was filtered off, washed with water, and
dried. It was crystallized from the proper solvent.
2-Nitrophenylazomalonic Acid Hydrazide (15a). Pale-yellow needles from methanol. Yield 98%; mp
258-259°C. IR spectrum, , cm–1: 3450, 3200 (NH2, NH), 1650 (C=O). 1H NMR spectrum, , ppm: 2.51 (1H, s,
CH); 7.93 (4H, m, Ar); 9.81 (4H, s, 2NH2); 13.76 (2H, br. s, 2NH). 13C NMR spectrum, , ppm: 38.2, 122.1,
124.3, 136.1, 172.1. Mass spectrum, m/z (Irel, %): 281 [M]+ (100). Found, %: C 38.51; H 4.01; N 34.77.
C9H11N7O4. Calculated, %: C 38.44; H 3.94; N 34.86.
434

2-Chlorophenylazomalonic Acid Hydrazide (15b). Yellow needles from methanol. Yield 98%; mp
221-222°C. IR spectrum, , cm–1: 3300, 3200 (NH2, NH), 1660 (C=O). 1H NMR spectrum, , ppm: 3.12 (1H, s,
CH); 6.91-7.35 (4H, m, Ar); 9.43 (4H, s, 2NH2); 10.62 (2H, s, NH). 13C NMR spectrum, , ppm: 39.2, 118.1,
123.0, 130.2, 175.2. Mass spectrum, m/z (Irel, %): 270 [M]+ (74), 238 (40), 152 (9), 139 (18), 129 (17), 128 (27),
127 (58), 126 (64), 125 (13), 111 (35), 40 (13), 32 (100). Found, %: C 40.12; H 4.15; Cl 13.22; N 31.16.
C9H11ClN6O2. Calculated, %: C 39.94; H 4.10; Cl 13.10; N 31.05.
Synthesis of 1-Acetyl-4-arylazo-3,5-pyrazolidinediones 16 (General Method). Arylazo malonic acid
hydrazide 15 (0.1 mol) was refluxed in glacial acetic acid for 2 h. The reaction mixture was poured on ice-water
and the resulting product was filtered off, washed with water, and dried. The pyrazolidenedione derivative was
crystallized from the proper solvent and the results are summarized as follows:
1-Acetyl-4-(2'-nitrophenylazo)-3,5-pyrazolidinedione (16a). Yellow needles from methanol. Yield
1
75%; mp 309-310°C. IR spectrum, , cm–1: 1690 (C=O), 1550 (NO2). H NMR spectrum, , ppm: 2.52 (3H, s,
COCH3); 3.12 (1H, s, CH); 7.54-8.22 (4H, m, Ar); 9.42 (1H, br. s, NH). 13C NMR spectrum, , ppm: 22.1,
112.0, 114.3, 118.2, 122.1, 162.4, 170.1. Mass spectrum, m/z (Irel, %): 291 [M]+ (2), 249 (100), 190 (5), 189 (6),
173 (20), 163 (13), 138 (21), 127 (47), 122 (11). Found, %: C 45.42; H 3.12; N 14.14. C11H9N5O5. Calculated, %:
C 45.37; H 3.11; N 14.05.
1-Acetyl-4-(2'-chlorophenylazo)-3,5-pyrazolidinedione (16b). Yellow needles from methanol. Yield
1
75%; 280-281°C. IR spectrum, , cm–1: 3200 (NH), 1690 (C=O). H NMR spectrum, , ppm: 2.51 (3H, s,
COCH3); 3.21 (1H, s, CH); 7.22-7.80 (4H, m, Ar); 9.32 (1H, br. s, NH). 13C NMR spectrum, , ppm: 22.0, 39.2,
118.2, 122.4, 126.1, 164.2, 175.4. Mass spectrum, m/z (Irel, %): 238 [M]+ (90), 237 (12), 202 (29), 153 (13), 151
(38), 139 (12), 128 (26), 127 (100), 126 (65), 125 (32), 111 (39), 101 (18), 99 (50), 69 (23). Found, %: C 47.22;
H 3.35; Cl 12.58; N 20.14. C11H9ClN4O3. Calculated, %: C 47.07; H 3.23; Cl 12.63; N 19.96.
Reduction of 4-Arylidene-3,5-pyrazolidinediones. Synthesis of 4-Benzyl-3,5-pyrazolidinediones
(General Method). A suspension of the 3,5-pyrazolidenedione derivative 6 (0.01 mol) in methanol (10 ml) was
refluxed with an aqueous solution of sodium borohydride (0.02 mol in 10 ml water) for 2 h. The reaction
mixture was cooled to room temperature and neutralized with diluted hydrochloric acid. The precipitated solid
was collected, washed thoroughly with water, and dried. It was crystallized from the proper solvent.
4-(4'-N,N-Dimethylaminobenzyl)-3,5-pyrazolidinedione (17). Grayish needles from dioxane. Yield
1
30%; mp 220-221°C. IR spectrum, , cm–1: 3410 (broad, OH, NH), 1655 (C=O). H NMR spectrum, , ppm
(J, Hz): 2.85 (6H, s, 2CH3); 2.91 (2H, d, J = 6.3, CH2); 3.21 (1H, t, J = 6.3, CH); 6.727.53 (4H, m, Ar); 7.62
(2H, br. s, 2NH). 13C NMR spectrum, , ppm: 28.7, 43.6, 66.1, 113.3, 128.8, 129.7, 141.7, 172.1. Mass
spectrum, m/z (Irel, %): 233 [M]+ (100). Found, %: C 61.78; H 6.51; N 18.14. C12H15N3O2. Calculated, %: C 61.79;
H 6.48; N 18.01.
1-Acetyl-4-(4'-nitrobenzyl)-3,5-pyrazolidinedione (18). Pale-brown needles from dioxane. Yield 31%;
mp 238-239°C. IR spectrum, , cm–1: 3200 (NH), 1680 (C=O), 1520 (NO2). 1H NMR spectrum, , ppm (J, Hz):
2.41 (3H, s, CH3); 3.07 (2H, d, J = 6.4, CH2); 3.76 (1H, t, J = 6.4, CH); 7.628.33 (4H, m, Ar); 8.91 (1H, br. s,
NH). 13C NMR spectrum, , ppm: 21.1, 43.3, 58.2, 116.1, 122.0, 124.3, 126.1, 175.2. Found, %: C 52.12; H 3.92;
N 15.23. C12H11N3O5. Calculated, %: C 51.99; H 4.00; N 15.16.
X-ray Analysis. X-ray crystal-structure determinations for compounds 6a,e and 10 (Table 1 and Fig.
1a,c). All measurements were conducted on a Nonius KappaCCD area detector diffractometer [41] using
graphite-monochromated MoKα radiation (λ 0.71073 Å) and an Oxford Cryosystems Cryostream 700 cooler. Data
reduction was performed with HKLDENZO and SCALEPACK [42]. The intensities were corrected for Lorentz
and polarization effects, but not for absorption, and equivalent reflections were merged. Each structure was
solved by direct methods using either SHELXL97 [43] or SIR92 [44], which revealed the positions of all non-
hydrogen atoms. The non-hydrogen atoms of each structure were refined anisotropically. The amide H-atoms
were placed in the positions indicated by a difference electron density map and their positions were allowed to
refine together with individual isotropic displacement parameters. All remaining H-atoms were placed in
435

geometrically calculated positions and refined using a riding model where each H-atom was assigned a fixed
isotropic displacement parameter with a value equal to 1.2 Ueq of its parent C-atom (1.5 Ueq for methyl groups).
The structures were refined on F2 using full-matrix least-squares procedures, which minimized the function
Σw(Fo –Fc2)2. A correction for secondary extinction was applied in the case of compound 6e. For compound 10
2
one low-angle reflection were omitted from the final refinement because the observed intensities of this
reflection was much lower than the calculated value as a result of being partially obscured by the beam slope.
Neutral atom scattering factors for non-hydrogen atoms were taken from [45], and the scattering factors for
H-atoms were taken from [46]. The values of the mass attenuation coefficients were those of [47]. All
calculations were performed using SHELXL97 [43]. The crystallographic diagrams were drawn using ORTEPII
[48]. CCDC-750291-750293, contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge crystallographic data centre via www.ccdc.cam.ac.uk/data-
request/cif.
The authors are grateful to Dr. Anthony Linden, Institute of Organic Chemistry, University of Zurich for
conducting the three crystal structure determinations.
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437