Synthesis of new fused and spiro heterocyclic systems from 3,5-pyrazolidinediones

Article abstract of DOI:10.1002/jccs.200400017

4-Bromo-1-phenyl-3,5-pyrazolidinedione 2 reacted with different nucleophilic reagents to give the corresponding 4-substituted derivatives 3-8. The cyclized compounds 9-11 were achieved on refluxing compounds 3, 4 or 6 _a in glacial acetic acid or diphenyl ether. 4,4-Dibromo-1-phenyl-3,5- pyrazolidinedione 12 reacted with the proper bidentates to give the corresponding spiro 3,5-pyrazolidinediones 13-15, respectively. The 4-aralkylidine derivatives 16_a-c, were subjected to Mannich reaction to give Mannich bases 17_a-c-22_a-c, respectively. 4-(p-Methylphenylaminomethylidine)-1-phenyl-3,5-pyrazolidinedione 23 or 4-(p-methylphenylazo)-1-phenyl-3,5-pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and N,S-acetals to give pyrano[2,3-c]pyrazole, pyrazolo[4′,3′:5,6]pyrano[2,3-c]pyrazole, spiropyrazole-4,3′-pyrazole and spiropyrazole-4,3′-[1,2,4]triazolane derivatives 24-34, respectively.

Full text of DOI:10.1002/jccs.200400017

Journal of the Chinese Chemical Society, 2004, 51, 103-114
103
Synthesis of New Fused and Spiro Heterocyclic Systems from
3,5-Pyrazolidinediones
M. A. Abdel-Rahman, A. Khodairy*, A.-B. A. G. Ghattas and S. Younes
Chemistry Department, Faculty of Science, Sohag 82524 , Egypt
4-Bromo-1-phenyl-3,5-pyrazolidinedione 2 reacted with different nucleophilic reagents to give the cor-
responding 4-substituted derivatives 3-8. The cyclized compounds 9-11 were achieved on refluxing com-
pounds 3, 4 or 6a in glacial acetic acid or diphenyl ether. 4,4-Dibromo-1-phenyl-3,5-pyrazolidinedione 12 re-
acted with the proper bidentates to give the corresponding spiro 3,5-pyrazolidinediones 13-15, respectively.
The 4-aralkylidine derivatives 16a-c, were subjected to Mannich reaction to give Mannich bases 17a-c-22a-c, re-
spectively. 4-(p-Methylphenylaminomethylidine)-1-phenyl-3,5-pyrazolidinedione 23 or 4-(p-methylphenyl-
azo)-1-phenyl-3,5-pyrazolidinedione 29 were prepared and reacted with active nitriles, cyclic ketones and
N,S-acetals to give pyrano[2,3-c]pyrazole, pyrazolo[4¢,3¢:5,6]pyrano[2,3-c]pyrazole, spiropyrazole-4,3¢-
pyrazole and spiropyrazole-4,3¢-[1,2,4]triazolane derivatives 24-34, respectively.
Keywords: 3,5-Pyrazolidinedione; Pyrazolo[3,4-b][1,4]thiazine; Imidazo[4,5-c]pyrazole and spiro
pyrazole-4¢,2-thiadiazole derivatives.
INTRODUCTION
The early discovery of biological effects for pyrazoli-
= 233.37 which is in agreement with its molecular formula
(cf. Scheme I, Table 1).
Refluxing of compounds 3 and 4 in glacial acetic acid
afforded the corresponding cyclized products pyrazolo[3,4-
b][1,4]thiazine (9) and imidazo[4,5-c]pyrazole (10) deriva-
tives, respectively, whereas pyrazolo[3,4-e][1,4]benzo[b]-
thiazine derivative (11) was obtained by refluxing compound
6a in diphenyl ether.17 Mass spectrum of compound 9 showed
a molecular ion peak at m/z = 235.18 (M++2) which is in
agreement with its molecular formula (cf. Scheme I, Table 1).
4,4-Dibromo-1-phenyl-3,5-pyrazolidinedione (12) is a
building block for the synthesis of spiro heterocyclic sys-
tems13 attached to pyrazolidinedione moiety, where it was
treated with ethylenediamine, ethanolamine, cystamine,
2-mercaptoethanol, o-phenylenediamine, o-aminophenol,
o-aminothiophenol or thiosemicarbazide to give the corre-
sponding spiro [imidazolidine-, oxazolidine-, thiazolidine-,
(1,3)oxathiolane]-2¢,4-pyrazole derivatives (13a-d), spiro
pyrazole-4¢,2-[benzimidazole, benzoxazole, benzothiazole,
(1,3)benzodioxole] (14a-d), and spiro pyrazole-4¢,2-thiadi-
azole (15), respectively. Mass spectra of compounds 13b, 14c
and 15 showed a molecular ion peak at m/z = 233 (M+), 300
(M++2), 263.29 (M+) which is in agreement with its molecu-
dinediones as analgesics,1 antipyretics,2 antrheumatics,3
antiphlogistic agents,4 for treatment of various other dis-
eases5-9 and as antiinflammatory drugs,10,11 prompted us to
continue our previous work on the synthesis of pyrazolo-
[3,4-b]pyridines,12 pyrazolo[3,4-b]thieno[3,2-e]pyridines,12
pyrazolodithiane13 and spiro heterocyclic systems.13 We re-
port herein synthesis of pyrazolothiazine, pyrano[2,3-c]pyr-
azole, spiro[imidazolidine-, oxazolidine-, thiazolidine-,
oxathiolane]-2¢,4-pyrazole derivatives, spiro pyrazole-4¢,2-
benzimidazole, spiro pyrazole-4¢,2-thiadiazole, spiro pyr-
azolopyrazole, and spiro pyrazole-triazolane derivatives.
RESULTS AND DISCUSSION
The parent compounds 1-phenyl-3,5-pyrazolidinedi-
one (1),14 4-bromo- (2)15 and 4,4-dibromo-1-phenyl-3,5-pyr-
azolidinedione (12)16 were prepared according to known
methods.
4-Bromo-1-phenyl-3,5-pyrazolidinedione (2) reacted
with cystamine, guanidine, ethyl glycinate, o-aminothio-
phenol, o-phenylenediamine, p-aminobenzoic acid or hydro-
quinone in dioxane in the presence of K2CO3 to give the cor-
responding 4-substituted derivatives 3-8, respectively. Mass
spectrum of compound 4 showed a molecular ion peak at m/z
lar structure (cf. Scheme II, Table 1).
18
4-Aralkylidene derivatives 16a-c
,
were subjected to
Mannich reaction, using amines such as piperidine, morpho-
line, piprazine, n-butylamine, n-propylamine or iso-propyl-
amine to give the corresponding Mannich bases 4-aralkyl-

104 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
Table 1. Characterization Data of the Prepared Compounds
Analytical Data b
Cal./ found
Comp M.P(°C)a Yield
Mol. For.
(Mol. Wt)
Spectral data
Crys.
No.
(%)
Solvent
C
H
N
S
3
4
195
(Benzene)
187
80
82
C11H13N3O2S
(251.30)
C10H11N5O2
(233.23)
52.57
52.39
51.50
51.54
5.21
5.34
4.75
4.73
16.72
16.99
30.03
30.19
12.76 IR: 3300 (NH); 3240; 3100 (NH2), 1710 (CO),
12.64 1670 (CO)amidic
.
IR: 3300-3100 (NH2+NH), 1708 (CO), 1676
(CO)amidic. Ms: 233.37 (M+, 0.7%); 216.4
(19.1%); 200.5 (13.5%); 190.5 (1.1%); 175.5
(69.8%); 77.8 (22%); 27.9 (16.9%).
Benzene
5
285
Benzene
230
60
89
C13H15N3O4
(277.28)
C15H13N3O2S
(299.35)
56.31
56.58
60.19
60.07
5.45
5.26
4.38
4.48
15.15
15.32
14.04
13.89
IR: 3240, 3160 (2NH), 1740 (CO)ester, 1708
(CO), 1676 (CO)amidic
.
6a
10.71 IR: 3300-3180 (NH2+NH), 1710 (CO), 1676
10.98 (CO)amidic 1H-NMR 7.4-6.5 (m, 11H, arom
+NH); 4.3-3.8 (br., 2H, NH2), 1.8 (s, 1H, CH).
IR: 3380, 3280 (NH2), 3100 (NH), 1700 (CO),
1660 (CO)amidic. 1H-NMR 7.2-6.3 (m, 10H,
arom. + NH); 5.8-5.6 (br., 2H, NH2), 2.3 (s,
1H, CH).
Benzene
6b
205
Ethanol
76
C15H14N4O2
(282.30)
63.82
63.75
5.00
5.18
19.85
19.83
7
8
175
Methanol
190
55
65
C16H13N3O4
(311.29)
C15H12N2O4
(284.27)
61.73
61.90
63.38
63.26
4.21
4.53
4.25
4.55
13.50
13.26
9.85
IR: 3420 (OH), 3200 (NH), 1720 (CO)acid.
1705 (CO); 1680 (CO)amidic
IR: 3400 (OH); 3180 (NH); 1700 (CO); 1670
(CO)amidic. 1H NMR 7-6.1 (m, 10H, arom
;
.
Benzene
9.62
+NH); 2.3 (s, 1H, CH); 1.2 (s, 1H, OH).
9
220
Methanol
70
C11H11N3OS
(233.29)
56.63
56.84
4.75
4.56
18.01
17.88
13.74 IR: 3300-3100 (NH); 1660 (CO)amidic. Ms:
13.98 235.18 (M++2, 0.1 %); 231.18 (M+-2, 0.1%);
219 (0.2%); 204.29 (0.5%); 192.3 (0.4%);
176.4 (0.8%); 76.8 (10.2%); 27.9 (16.1%).
10
185
Ethanol
230
Methanol
220
Ethanol
194
Ethanol
75
76
56
79
C10H9N5O
(215.21)
C21H13N5OS
(383.43)
C11H12N4O2
(232.24)
C11H11N3O3
(233.22)
55.81
55.68
64.04
63.98
56.89
56.67
56.65
56.46
4.21
4.40
3.94
3.72
5.21
5.43
5.19
5.43
32.54
32.28
14.94
15.12
24.12
24.34
24.12
24.30
IR: 3320-3100 (NH2+2NH); 1687 (CO)amidic.
11
11.40 IR: 3300 (NH), 3100 (NH), 1680 (CO)amidic.;
1156
1H NMR 7.2-6.4 (m, 11H, arom +2NH).
IR: 3300-3100 (3NH), 2980 (CH)aliph. 1706
13a
13b
(CO); 1660 (CO)amidic.
IR: 3300, 3180 (2NH); 1710(CO); 1680
(CO)amidic. 1H-NMR 7.4-6.5 (m, 7H, arom
+2NH); 4.5-4.2 (t, 2H, CH2); 3.8-3.6 (t, 2H,
CH2). Ms: 236(M++3, 21%); 176 (18%); 77
(100%); 58(52%) 27.9 (16.1%).
13c
13d
240
Ethanol
210(decom) 65
Ethanol
81
C11H11N3O2s
(249.29)
C11H10N2O3S
(233.23)
53.00
53.25
52.79
52.90
5.21
5.11
4.03
4.22
24.12
24.43
11.19
11.00
12.86 1H-NMR 7.8-7.2 (m, 7H, arom +2NH); 4.3-4.1
12.64 (t, 2H, CH2); 3.3-3.0 (t, 2H, CH2).
12.81 1H-NMR 7.9 (s, 1H, NH); 7.7-6.8 (m, 5H,
12.90 arom); 3.6-3.3 (t, 2H, CH2); 2.9-2.7 (t, 2H,
CH2).
14a
14b
14c
14d
15
262
Ethanol
240
Ethanol
180
Benzene
230
Benzene
240
70
60
84
72
52
C15H12N4O2
(280.28)
C15 H11N3O3
(281.27)
C15H10N3O2S
(298.31)
C15H10N2O4
(282.25)
64.28
64.45
64.10
64.00
60.40
60.24
63.83
63.68
45.62
45.48
4.32
4.13
3.94
3.75
3.38
3.59
3.57
3.80
3.45
3.22
19.99
19.82
14.94
15.12
14.09
14.17
9.93
9.67
26.60
26.95
IR: 3388, 3306, 3200 (3NH); 3072 (CH)
arom., 1700 (CO); 1660 (CO)amidic
IR: 3300-3100 (2NH); 3060 (CH) arom., 1705
(CO); 1676 (CO)amidic
10.75 IR: 3330-3160 (2NH); 3040 (CH) arom., 1700
10.62 (CO); 1665 (CO)amidic
IR: 3280 (NH); 3050 (CH) arom., 1710 (CO);
1676 (CO)amidic
12.18 IR: 3420-3280 (NH2, -NH); 3100 (NH); 1710
12.34 (CO); 1670 (CO)amidic
C10H9N5O2S
(263.27)
Benzene

Heterocyclic Synthesis from 3,5-Pyrazolidinediones
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 105
17a
17b
285
Pet. ether
250
65
68
C18H23N3O2
(313.40)
C20H22N4O2
(350.42)
68.99
68.69
68.55
68.96
7.40
7.62
6.33
6.03
13.41
13.52
15.99
15.66
IR: 3060 (CH) arom., 2972, 2860 (CH)aliph.
1708 (CO); 1685 (CO)amidic
,
IR: 3200 (NH)pyrrole; 3060 (CH)arom.; 2940
Benzene
(CH)aliph. 1H-NMR: 9.3 (s, 1H, =CH); 7.8-7.2
(m, 9H, 5H of arom., 3H of pyrrole and 1H of
NH); 4.1 (s, 2H, CH2-N); 3.1-2.8 (br., 10H,
5CH2).
17c
254
Ethanol
70
C23H25N3O3
(391.47)
70.57
70.98
6.44
6.54
10.73
10.43
1H-NMR: 7.3 (s, 1H, =CH); 7.1-6.3 (m, 9H,
arom.); 4.4 (s, 2H, N-CH2-N), 3.8 (s, 3H,
CH3), 3.6-3.2 (br., 4H, 2N-CH2); 2.3 (m, 6H,
3CH2).
18a
18b
250
Pet. ether
255
80
77
C17 H21N3O3
(315.37)
C19H20N4O3
(352.39)
64.75
64.56
64.67
64.92
6.71
6.43
5.72
5.94
13.32
13.63
15.90
15.63
IR: 3050 (CH)arom.; 2965 (CH)aliph.; 1705 (CO);
1679 (CO)amidic
.
IR: 3225 (NH)pyrrole; 1700 (CO), 1660
(CO)amidic. MS: m/z = 353.3 (M+1, 11%); 282
(18%); 274 (64%); 257 (100%); 241 (29%).
IR: 3050 (CH)arom.; 2965 (CH)aliph.; 1705 (CO);
1679 (CO)amidic.. 1H-NMR; 7.3-6.2 (m, 10H,
arom., + =CH); 4.6 (s, 2H, N-CH2-N); 4.1 (s,
3H, CH3); 3.8-3.6 (t, 4H, O.(CH2)2); 3.5-3.2 (t,
4H, -N(CH2)2).
Ethanol
18c
19a
240
Benzene
82
89
C22 H23N3O4
(393.44)
67.16
67.39
5.48
5.24
12.03
12.23
175
Methanol
C40 H38N6O6
(698.77)
68.76
68.43
5.48
5.98
12.03
12.31
IR: 3050 (CH)arom.; 1700 (CO); 1676
(CO)amidic. MS: m/z = 545.3 (M++1, 18%);
491.3 (7%); 477.3 (43%); 417.2 (86%); 387.2
(100%); 369.2 (46%); 274 (7%); 257 (27%);
241.1 (23%).
19b
19c
20a
240
Ethanol
88
92
85
C34H32N8O4
(616.68)
66.32
66.64
5.23
5.14
10.38
10.63
1H-NMR; 7.6 (s, 2H, 2=CH); 7.2-6.4 (m, 18H,
arom. +2NH); 4.1 (s, 4H, 2-N-CH2N); 3.6-3.2
(br., 8H, 4CH2).
260
Ethanol
C30H34N6O4
(542.63)
66.41
6.32
6.13
15.49
15.98
1H-NMR; 7.3-6.5 (m, 18H, arom. + =CH); 4.2-
4 (br., 4H, 2 N-CH2-N); 3.6-3 (br., 8H, 4CH2);
1.3 (s, 6H, 2CH3).
285
Dioxane
C17H23N3O2
(301.39)
67.75
67.54
7.69
7.97
13.94
13.69
IR: 3059 (CH)arom., 2867 (CH)aliph., 1710 (CO);
1668 (CO)amidic. MS: m/z =301 (39%); 278.2
(21%); 276.2 (80%); 271.2 (100%); 257
(21%); 241.2 (45%); 216 (24%); 215.2 (71%).
IR: 3070 (CH)arom., 2965 (CH)aliph., 1710 (CO);
20b
20c
21a
270
Dioxane
140
Ethanol
240
78
87
70
C19 H22N4O2
(338.41)
C22H25N3O3
(379.46)
C16H21N3O3
(324.39)
67.44
67.88
69.64
69.92
66.88
66.42
6.55
6.35
6.64
6.41
7.37
7.54
16.65
16.42
11.07
11.35
14.62
14.98
1656 (CO)amidic
IR: 3040 (CH)arom., 2856 (CH)aliph., 1700 (CO);
1676 (CO)amidic
.
.
MS: m/z =286.2 (M-1, 6%); 285.2 (11%); 274
(35%); 262 (32%); 257 (42%); 243.2 (100%);
241 (27%); 215.1 (47%).
Benzene
21b
21c
175
Methanol
240
82
76
C18H20N4O2
(325.39)
C21H14N3O3
(365.43)
66.44
66.76
69.02
69.32
6.20
6.02
6.34
6.65
17.22
17.64
11.50
11.21
IR: 3065 (CH)arom., 2940 (CH)aliph., 1708 (CO);
1665 (CO)amidic
.
1H-NMR; 9.6 (s, 1H, =CH); 8.5-8.1 (m, 9H,
arom.); 7.1 (s, 1H, NH); 5.5-5.2 (br., 2H, N-
CH2-N); 3.7 (s, 3H, OCH3); 3.1 (s, 2H, CH2-
NH); 1.6-1.4 (br., 4H, 2CH2); 1.1 (t, 3H, CH3).
IR: 3045 (CH)arom., 2961, 2860 (CH)aliph., 1706
Ethanol
22a
22b
22c
260
Ethanol
285
Dioxane
270
68
73
78
C16H21N3O2
(287.36)
C18H20N4O2
(325.39)
C21H23N3O3
(265.43)
66.68
66.24
66.44
66.86
69.02
69.41
7.37
7.53
6.20
60.42
6.34
6.13
14.62
14.76
17.22
17.03
11.50
11.87
(CO); 1684 (CO)amidic
IR: 3050 (CH)arom., 2887 (CH)aliph., 1700 (CO);
1657 (CO)amidic
.
.
MS: m/z = 366,4 (M+1, 15%); 364.4 (15%);
347.3 (17%); 334.2 (21%); 319 (43%); 276.2
(47%); 274 (43%); 257 (100%); 241 (42%);
15.1 (56%).
Dioxane

106 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
23
24
25
310
Dioxane
93
80
67
C17 H15N3O2
(293.32)
69.61
69.41
5.50
5.33
14.33
14.47
IR: 3280, 3120 (2NH); 2930 (CHaliph. ) ; 1708
(CO), 1665 (COamidic ). 1H-NMR: 9.2 (s, 1H,
NH); 7.8-6.4 (m, 10H, arom.+ NH), 5.6 (s,
1H,=CH); 1.8 (s, 3H, CH3 ). MS: 294 (M+ +1;
2.5%), 293 (M+; 12.4%), 292 (M+-1; 1%).
247
ethanol
C20H17N5O2
(359.39)
66.84
66.98
4.77
4.59
19.49
19.38
IR: 3240 (NH); 3140 (NH); 3050 (CH)arom.;
2857 (CH)aliph.; 2203 (CN); 1705 (CO); 1647
(CO)amidic. 1H NMR; 9.1 (s, 1H, NH); 7.1-6.4
(m, 10H, arom. +NH); 4.2 (s, 1H, CH); 3.3 (s,
2H, NH2); 1.6 (s, 3H, CH3).
IR: 3340-3140 (4NH);1678, 1647 (2 CO)amidic.
MS: 373.94 (M+ -1; 0.2%), 360.96 (2.0%), 345
(0.7%), 326 (0.6%),293.2 (24.9%), 292.2
(100%), 278.25 (0.8%), 177.49 (12.3%),
175.53 (11.1%), 76.8 (76.8%), 27.92 (8.5%).
IR: 3320-3160 (3NH); 3040 (CH)arom.; 2957
(CH)aliph.; 1670, 1647 (2CO)amidic.
280
methanol
C20 H17N5O3
(375.38)
63.99
64.10
4.57
4.36
18.66
18.54
26
185
methanol
180
methanol
262
67
60
68
C
26 H21N5O3
(451.48)
69.17
69.34
72.15
72.03
73.52
73.46
4.69
4.54
5.16
5.30
5.89
5.76
15.51
15.46
19.85
19.83
11.69
11.98
27
C27H23N5O2
(449.51)
C22H21N3O2
(359.43)
IR: 3260 (NH); 3150 (NH); 3055 (CH)arom.
2860 (CH)aliph.; 1647 (CO)amidic.
;
28a
IR: 3121 (NH); 3045 (CH)arom.; 2941, 2858
(CH)aliph.; 1705 (CO); 1647 (CO)amidic 1H-
NMR: 7.2-6.3 (m, 10H, arom. +NH); 4.1 (s,
2H, CH2); 3.5-3.2 (m, 2H, CH2); 2.6-2.4 (m,
4H, 2CH2); MS: 360.7 (M++1, 0.2%); 341.7
(1.9%); 292.7 (20.0%); 271.8 (20.4%); 270.8
(100.0%); 197.9 (5.3%); 176.8 (0.4%); 76.9
(9.7%).
ethanol
28b
28c
30
185
methanol
265
ethanol
270
82
62
C23H23N3O2
(373.45)
C24H25N3O2
(387.48)
C19H16N6O2
(360.39)
73.97
73.84
74.40
74.56
63.32
63.20
6.21
6.34
6.50
6.38
4.48
4.63
11.25
11.34
10.84
10.96
23.32
23.40
IR: 3280 (NH); 3160 (NH); 3040 (CH)arom.
2932, 2850 (CH)aliph.; 1643 (CO)amidic.
IR: 3240 (NH); 3110 (NH); 3031 (CH)arom.
2946, 2863 (CH)aliph.; 1649 (CO)amidic.
IR: 3300-3100 (NH2 + 2NH); 2880 (CH)aliph.
2193 (CN); 1710 (CO);1662 (CO)amidic 1H
;
;
;
ethanol
NMR; 8.3 (s, 1H, NH); 7.8-7.2 (m, 10H, arom.
+ NH); 4.8-4.4 (br., 2H, NH2); 1.8 (s, 3H,
CH3) MS: 359 (M+-1, 4.1%); 294 (80%); 2.3
(4.1%); 176.8 (2.5%); 119 (29.5%); 108
(88.1%) 91 (79.1%); 77 (86%); 28 (100%).
IR: 3139 (NH); 3069 (CH)arom.; 2850
(CH)aliph.;2196 (CN); 1710 (CO); 1641
(CO)amidic
IR: 3280, 3150 (2NH); 3057 (CH)arom.; 2853
(CH)aliph.; 1700 (CO); 1674 (CO)amidic 1H
NMR: 8.3 (s, 2H, 2NH); 8.0-7.3 (m, 11H,
arom. +NH); 4.2 (s, 1H, NH); 1.7 (s, 3H, CH3)
31
32
324
ethanol
62
70
C27H20N6O2
(460.49)
70.42
70.40
4.38
4.23
18.25
18.40
236
ethanol
C25H20N6O3
(452.47)
66.36
66.21
4.46
4.62
18.57
18.48
33
34
200
benzene
278
42
68
C26H22N6O2
(450.50)
C28H24N6O4
(508.53)
69.32
69.21
66.13
66.25
4.92
5.07
4.76
4.98
18.66
18.78
16.53
16.37
IR: 3150 (NH); 3065 (CH)arom.; 2920 (CH)aliph.
1710 (CO); 1651 (CO)amidic
IR: 3360, 3200 (2NH); 3060 (CH)arom.; 2860
(CH)aliph; 2210 (CN); 1740 (CO)ester; 1700
(CO); 1660 (CO)amidic
;
ethanol

Heterocyclic Synthesis from 3,5-Pyrazolidinediones
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 107
Scheme I
S
SCH2CH2NH2
AcOH
O
O
H2NCH2CH2SH
reflux
HN
HN
OH
N
N
Ph
N
H
Ph
3
9
NH
H
N
-
-
NH C NH2
O
NH
O
O
AcOH
reflux
-
-
H2N C NH2
NH2
HN
HN
OH
HN
N
Ph
N
O
N
Ph
N
Ph
4
10
1
O
O
NHCH2COOEt
OH
H2NCH2COOEt
N Br
CHCl3
HN
PTC
N
Ph
O
Br
O
5
HN
O
N
XH
YH
X
Ph
O
S
O
HY
OH
PhOPh
reflux
2
HN
HN
N
Ph
N
Ph
N
H
6a,b
11
6 , X=S , Y=NH
a
6 , X=Y=NH
b
H
N
O
COOH
H2N
COOH
HN
OH
N
Ph
7
O
O
OH
HO
OH
HN
OH
N
Ph
8
idene-2-(N-piperidino-, morpholino-, piprazine, n-butyl-,
n-propyl- and isopropyl)aminomethyl-1-phenylpyrazoli-
dine-3,5-diones (17a-c-22a-c), respectively. Mass spectra of
compounds 17b, 18b, 19a, 20a, 21a and 22c showed the molec-
ular ions at m/z (rel. int. %): 350 (77), 352 (11), 342 (18), 301
(54), 287 (12) and 365 (21), respectively (cf. Scheme III, Ta-
ble 1).
4-(p-Methylphenylaminomethylidine)-1-phenyl-3,5-
pyrazolidinedione (23) was prepared from the reaction of
compound 1 with ethyl orthoformate and p-toluidine in boil-

108 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
Scheme II
XH
X
O
YH
Y
O
Dioxane/ K2CO3
HN
O
N
HN
Ph
O
N
Ph
13a , X=Y=NH
b , X=NH , Y=O
c , X=NH , Y=S
d , X=S , Y=O
13a-d
1
Br2/ AcOH
X
XH
1:2
Br
O
O
Y
YH
Br
HN
Dioxane/ K2CO3
O
N
Ph
HN
O
N
Ph
14a , X=Y=NH
b , X=NH , Y=O
c , X=NH , Y=S
d , X=Y=O
14a-d
12
NH2
N
S
S
O
-
-
H2NNH C NH2
N
H
HN
Dioxane/ K2CO3
O
N
Ph
15
ing dimethylformamide (Eq. 1). Mass spectrum of the prod-
uct showed a molecular ion peak at m/z = 294 (M++1) which
is in agreement with its molecular structure.
m/z = 359.05 (M+), 373.94 (M+-1), and 360.7 (M++1) which
are in agreement with their molecular formulae (cf. Scheme
IV, Table 1).
The reaction pathway of compound 24 was assumed to
follow a preliminary formation of carbanion of the active
methylene reagent, which was added to the double bond fol-
lowed by a nucleophilic attack of the NH group at the CN,
CO, and CS groups with the elimination of a water molecule
in the case of cyanoacetamide and a H2S molecule in the case
of cyanothioacetamide.19 In the case of reaction of compound
23 with cyanoacetic hydrazide, evolution of NH3 gas was ob-
served with subsequent formation of fused pyrazolone ring
most probably via a nucleophilic attack of the NHNH2 group
at the C-NH2 linkage of the pyran nucleus followed by
cyclization into compound 2520 (cf. Scheme V).
NH2
OEt
-
-
O
CH NH
HC OEt
OEt
CH3
O
CH3
DMF
HN
HN
O
O
N
Ph
N
Ph
(1)
23
1
The reaction of compound 23 with active nitriles and
cyclic ketones, namely malononitrile, cyanoacetamide, cy-
anothioacetamide, cyanoacetic hydrazide, 1-phenyl-3,5-pyr-
azolidinedione, 3-methyl-1-phenyl-5-pyrazolone, cyclopen-
tanone, cyclohexanone and cycloheptanone in the presence
of a catalytic amount of triethyl amine gave pyrano[2,3-
c]pyrazoles derivatives (24-28), respectively. Mass spectra
of compounds 24, 25 and 28a showed molecular ion peaks at
The reaction of 4-(p-methylphenylazo)-1-phenyl-3,5-
pyrazolidinedione 2921,22 with active methylene reagents,
namely malononitrile, cyanoacetamide, cyanothioacetamide,
1-phenyl-3,5-pyrazolidinedione and 3-methyl-1-phenyl-5-
pyrazolone in the presence of a catalytic amount of triethyl

Heterocyclic Synthesis from 3,5-Pyrazolidinediones
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 109
Scheme III
R1
O
R
NH
CH2O ,
Dioxane
N
CH2
N
O
N
Ph
17
a-c
R1
O
R
O
NH
CH2O ,
O
N
CH2
N
Dioxane
O
N
Ph
18
a-c
R1
R1
O
O
R
R
HN
NH
Ph N
N Ph
N
CH2O ,
O
R1
O
N
O
O
N
Dioxane
O
R
N
HN
O
N
Ph
16
19
a-c
R1
O
a-c
R
CH (CH ) NH
Dioxane
CH2O ,
3
2
3
2
N
CH2
CH3(CH2)3NH
N
Ph
20
a-c
R1
O
R
CH O ,
CH3 (CH2) 2NH2
Dioxane
2
CH2
N
CH3(CH2)2NH
N
Ph
21
a-c
R1
O
R
(CH3) 2CH NH2
Dioxane
CH2O ,
CH2
N
(CH3)2CHNH
O
N
Ph
22
a-c
a, R , R1= CH3; b, R= H, R1= pyrrolyl;
c, R= H, R1= p-methoxyphenyl
amine gave spiropyrazole derivatives 30-32, respectively.
Mass spectrum of compound 30 showed a molecular ion peak
at m/z = 359 (M+-1) which is in agreement with its molecular
structure (cf. Scheme VI, Table 1).
Suggested mechanism for the formation of compound
30 is illustrated as follows19 (cf. Scheme VII).

110 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
Scheme IV
CN
CH2
-
Ar
NH
O
CN
O
Y
Dioxane/TEA
Y = CN, CONH2,
CSNH2
HN
NH2
N
Ph
24
-
NH Ar
O
O
CNCH2CONHNH2
HN
NH
Dioxane/TEA
N
H
N
O
Ph
25
O
-
-
-
O
CH NH
CH3
NH Ar
HN
O
N
Ph
O
O
HN
O
N
Dioxane/TEA
HN
NH
Ph
N
N
O
23
Ph
Ph
26
H3C
-
Ar
NH
O
N
O
N
Ph
CH3
O
HN
N
Dioxane/TEA
N
N
Ph
Ph
27
O
-
Ar
NH
O
O
( )n
( )n
Dioxane/TEA
HN
N
Ph
28
a-c
n= 1, 2,3
Ar = p-tolyl
The reaction of compound 29 with PhNCS and ethyl
cyanoacetate in 1:1:1 molar ratio under phase transfer cataly-
sis conditions (PTC)13,23 [dioxane/K2CO3/tetrabutylammo-
nium bromide (TBAB)] gave the corresponding spiro pyr-
azole-4,3¢-[1,2,4]triazolane 33 and spiro pyrazole-4,3¢-
[1,3,4]thiadiazolane 34 derivatives, respectively. Compound
33 was also obtained from the reaction of compound 29 with
N-,S-acetal in glacial acetic acid. IR spectrum of compound

Heterocyclic Synthesis from 3,5-Pyrazolidinediones
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 111
Scheme V
NHAr
CH
NHAr
-
O
-
O
CH NH
CH3
CNCH2CONH2
CH
O
CH CN
CH CN
CNCH2CSNH2
C
S
HN
HN
C
O
HN
O
O
O
N
N
N
NH2
NH2
Ph
Ph
Ph
23
CH2(CN)2
NHAr
CH
O
NHAr
CH
-
NH
O
Ar
CN
CH CN
C SH
NH
O
O
CH CN
HN
N
OH
-H2S
- H2O
C
HN
OH
NH
HN
Ph
NH2
N
OH
N
Ph
Ph
24
NHAr
CH
-
-
O
CH NH
CH3
NHAr
CH
O
CH CONHNH2
O
CNCH2CONHNH2
CH CONHNH2
HN
O
HN
CN
N
O
C
HN
N
Ph
N
OH
Ph
N
Ph
23
NH Ar
O
NH Ar
O
O
C
O
O
O
NH
NH
-
NH3
NH2
HN
HN
N
H
NH2
N
N
Ph
Ph
25
Ar = p-tolyl
33 showed the absorption bands at 2210 cm-1 corresponding
to the CN group and at 1740 cm-1 due to (CO)ester. Mass spec-
trum of compound 33 showed a molecular ion peak at m/z =
508.96 (M++1) which is in agreement with its molecular for-
mula (cf. Scheme VIII, Table 1).
were measured on a Jeol JMS-600 Shimadzu spectrophoto-
meter operating at 70 eV, using a direct inlet system. Elemen-
tal analyses (C,H,N) were carried out on a Perkin-Elmer 240
C elemental analyzer. Sulfur analyses were determined using
the oxygen flask method by the Microanalytical Unit at
Assiut University.
EXPERIMENTAL
Synthesis of 1-phenyl-4-substituted-3,5-pyrazolidine-
diones (3-8): (General procedure)
All melting points were determined on a Kofler melting
points apparatus and were uncorrected. IR spectra were ob-
tained on a Nicolet 710 FT-IR spectrometer. 1H-NMR spectra
were recorded on a Varian EM 360 A at 60 MHz using TMS
as an internal reference and (DMSO-d6) as a solvent. The MS
A mixture of anhydrous potassium carbonate (3 gm),
dry dioxane (30 mL), compound 2 (0.01 mol, 2.55 gm) and
the appropriate reactant (0.01 mol), namely cystamine hydro-
chloride (0.99 gm), guanidine hydrochloride (1.02 gm), ethyl
glycinate hydrochloride (1.40 gm), o-phenylenediamine

112 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
Scheme VI
NH2
CN
CH2
NC
-
CH3
N
O
Y
N
H
Dioxane/TEA
Y = CN, CONH2,
HN
O
N
CSNH2
Ph
30
H
N
-
N
Ph
O
O
HN
-
-
O
NH NH
CH3
O
N
Ph
N
CH3
O
N
H
HN
O
Dioxane/TEA
N
HN
O
N
Ph
Ph
31
29
N
-
N
Ph
H3C
H3C
N
O
N
CH3
N
Ph
O
N
H
Dioxane/TEA
HN
O
N
Ph
32
Scheme VII
O
C
S
C
NC
NC
CH
NH2
-
N
NH
-
CH
NH2
O
CH3
O
O
CNCH2CSNH2
CH3
CNCH2CONH2
N
N
HN
-
NH
CH3
-
O
H
HN
NH
HN
N
H
N
Ph
O
O
N
Ph
29
Ph
CH2(CN)2
OH
C
SH
C
NC
NH2
NH2
NC
NC
C
NH2
C
-
N
CH3
O
O
H
O
H
N
H
N
H
-H2S
CH3
N
H
-H2O
-
N
HN
HN
CH3
O
-
N
HN
O
N
N
Ph
O
N
Ph
Ph
30
(1.08 gm), o-aminothiophenol (1.25 mL), p-aminobenzoic
acid (1.37 gm) or hydroquinone (1.10 gm) was refluxed for 4
hrs.; the reaction mixture was filtered off, and the filterate
evaporated. The residue was triturated with pet. ether (40-60
°C) to give a solid, which crystallized from the appropriate
solvent to give the corresponding compounds 3-8, respec-

Heterocyclic Synthesis from 3,5-Pyrazolidinediones
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 113
Scheme VIII
NC
COOEt
PTC
CNCH2COOEt
+
PhNCS
KS
NHPh
CH3
-
-
N
NH
O
HN
N
O
Ph
CN
CN
29
C
C
COOEt
COOEt
Ph
N
S
-
N
CH3
N
CH3
O
O
N
H
N
H
+
HN
HN
O
O
N
N
Ph
Ph
33
34
-
-
NC
O
N NH
CH3
+
COOEt
NHPh
AcOH
HN
O
N
MeS
Ph
29
tively (cf. Scheme I, Table 1).
dioxane (30 mL), and anhydrous potassium carbonate (3.0
gm) was treated with a suitable reactant (0.01 mol), namely
ethylenediamine (0.60 mL), ethanolamine (0.61 mL), cyst-
amine hydrochloride (0.99 gm), 2-mercaptoethanol (0.78
mL), o-phenylenediamine (1.08 gm), o-aminophenol (1.10
gm), o-aminothiophenol (1.24 gm), catechol (1.10 mg) or
thiosemicarbazide (0.91 gm). The reaction mixture was
refluxed for 5 hrs.; the reaction mixture was filtered off and
the filterate evaporated. The solid residue was washed with
water and crystallized from the appropriate solvent to give
the corresponding compounds 13-15, respectively (cf.
Scheme II, Table 2).
Synthesis of 3-oxo-1-phenyl-1,2,3,5,6,7-hexahydropyr-
azolo[3,4-b][1,4]thiazine (9) and 5-amino-3-oxo-1-
phenyl-1,2,3,4-tetrahydroimidazo[4,5-c]pyrazole (10):
(General procedure)
0.005 Mol of compound 3 (1.23 gm) or 4 (1.17 gm) was
refluxed in glacial acetic acid for 4 hrs.; after cooling, the re-
action mixture was poured into ice. The separated solid was
collected by filtration and recrystallized from the suitable
solvent to give the corresponding compounds 9 and 10, re-
spectively (cf. Scheme I, Table 2).
Synthesis of 3-oxo-1-phenyl-1,2,3,9-tetrahydrobenzo[b]-
pyrazolo[3,4-e][1,4]thiazine (11)
Synthesis of compounds 17a-c-22a-c: (General procedure)
To a stirred solution of compounds 16a-c (0.01 mol) in
dioxane (20 mL), formaline solution (1 mL) and the appropri-
ate amine, namely (0.01 mol) including, piperidine (0.85
mL), morpholine (0.87 mL), piperazine (0.005 mol, 0.43
gm), n-butylamine (0.73 mL), n-propylamine (0.59 mL) or
isopropylamine (0.59 mL) were added. The reaction mixture
was refluxed for 3 hours. The precipitated solid was filtered
off, washed with water, and crystallized from the appropriate
solvent to give the corresponding compounds 17a-c -22a-c, re-
0.005 Mol of compound 6a (1.41 gm) was dissolved in
diphenyl ether (15 mL) and refluxed for 1.5 hr.; after cooling,
the reaction mixture was poured into pet. ether (40-60 ºC). The
separated solid was collected by filtration and recrystallized
from benzene to give compound 11 (cf. Scheme I, Table 2).
Synthesis of componds 13-15: (General procedure)
A mixture of compound 12 (0.01 mol, 3.34 gm), dry

114 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Abdel-Rahman et al.
spectively (cf. Scheme III, Table 2).
0.68 mL) was stirred for 2 hours at 60 °C. Compound 29
(0.005 mol, 1.47 gm) was added to the reaction mixture,
stirred for 5 hours at 70 °C. The reaction mixture was filtered
off and the filterate evaporated in vacuo. The residual solid
was washed with water, and dried and crystallized from etha-
nol to give compound 33. The cabonate layer was dissolved
in water (100 mL); the precipitated product was filtered off,
dried and crystallized from ethanol to give compound 34 (cf.
Scheme VIII, Table 2).
Synthesis of 4-(p-methylphenylaminomethylidine)-1-
phenyl-3,5-pyrazo-lidinedione (23)
A mixture of compound 1 (0.01 mol, 1.76 gm), p-
toluidine (0.01 mol, 1.08 gm) and ethyl orthoformate (0.01
mol, 1.67 mL) was heated for 0.5 hr.; the reaction mixture
was cooled to room temperature, and the formed precipitate
was filtered off and recrystalized from dioxane to give com-
pound 23 (cf. Eq. 1, Table 2).
Synthesis of Compounds 24-28: (General procedure)
Compound 23 (0.005 mol, 1.47 gm) was added to a
stirred solution of the appropriate reagent (0.005 mol), such
as malononitrile (0.33 mL), cyanoacetamide (0.42 gm),
cyanothioacetamide (0.5 gm), cyanoacetic hydrazide (0.50
gm), 1-phenyl-3,5-pyrazolidinedione (0.88 gm), 3-methyl-
1-phenyl-5-pyrazolone (0.88 gm), cyclopentanone (0.42
mL), cyclohexanone (0.49 mL) and cycloheptanone (0.61
mL) in dry dioxane (30 mL), in the presence of a catalytic
amount of triethylamine. The reaction mixture was refluxed
for 5 hours, then cooled to room temperature; the solid was
filtered off and recrystallized from the appropriate solvent to
give compounds 24-28, respectively. (cf. Scheme IV, Table 2).
Received February 10, 2003.
REFERENCES
1. Mayer, J.; Nemeck, O. Czch. 1963, 106, 252.
2. Tawab, S.; Moustafa, A.; Kira, M. Nature 1960, 186, 165.
3. Geigy, J. R. A-G. Brit. Pat. 1963, 921, 467; Swiss Appl. Aug.
1959, 34.
4. Mayer, J.; Ctvrtnik, J.; Nemeck, O. Czeh. 1962, 103, 65.
5. Leonard, G. C. Brit. Med. J. 1953, 1, 1311.
6. Benstead, J. G. Brit. Med. J. 1953, 1, 711.
7. Johnson, B. M.; Larkin, I. M. Brit. Med. J. 1954, 2, 1088.
8. Etess, A. D.; Jacobson, A. S. J. Amr. Med. Assoc. 1953, 151,
639.
9. Hinz, C.; Lamont-Havers, R. W.; Cominsky, B.; Gaines, L.
M. J. Amr. Med. Assoc. 1953, 151, 38.
10. D’Alo, G.; Conti, G.; Gadel, S.; Dalla Vedova, R. Farmaco,
Ed. Sci. 1978, 33(2), 106.
11. Abdelmajid, C.; Houda, F.; Cuong Luu Duc. Ann. Pharm.
Fr. 1980, 38(5), 429.
12. Ghattas, A.-B. A. G.; Abdel -Rahman, M. A.; Khodairy, A.;
Younes, S. Phosphorus, Sulfur and Silicon 2003, 178.
(Proof).
13. Khodairy, A. Phosphorus, Sulphur and Silicon 2000, 160,
159.
14. Preliez, D.; Arct, B. Acta Pol. Pharm. 1968, 25, 207.
15. Chapman, N. B.; Williams, T. F. A. J. Chem. Soc. 1952,
5044.
Synthesis of Compounds 30-32: (General procedure)
Compound 29 (0.005 mol, 1.47 gm) was added to a
stirred solution of the appropriate reagent (0.005 mol),
namely malononitrile (0.33 mL), cyanoacetamide (0.42 gm),
cyanothioacetamide (0.5 gm), cyanoacetic hydrazide (0.50
gm), 1-phenyl-3,5-pyrazolidinedione (0.88 gm) and 3-meth-
yl-1-phenyl-5-pyrazolone (0.88 gm) in dry dioxane (30 mL),
in the presence of a catalytic amount of triethylamine. The re-
action mixture was refluxed for 5 hours, then cooled to room
temperature; the solid was filtered off and recrystallized from
the proper solvent to give compounds 30-32, respectively.
(cf. Scheme VII, Table 2).
16. Asher. Ber. 1897, 1018.
17. Abdel-Ghany, H.; El-Sayed, A. M.; Khodairy, A.; Salah, H.
Synth. Comm. 2001, 31, 2523.
18. Mustafa, A.; Sammour, A.; Kira, M.; Hilmy, M. K.; Anwar,
M.; Nakhla, S. N. Arch. Pharm. 1965, 298(8), 516.
19. El-Saghier, A. M. M.; Khodairy, A. Phosphorus, Sulphur
and Silicon 2000, 160, 105.
20. El-Shafei, A. K.; Sultan, A. A.; Soliman, A. M.; Ahmed, E.
A. Synth. Comm. 1995, 25, 3211.
Synthesis of 5-cyanoethoxycarbonylmethylidene-
1,1¢,2¢,3,3¢,4,5¢-heptahydro-1¢,4-diphenyl-1-p-tolylspiro-
(pyrazole-4¢,3-[1,2,4]triazole)-3¢,5¢-dione] (33) and
5-cyanoethoxycarbonylmethylidene-1,1¢,2¢,3,3¢,5¢-hexa-
hydro-1¢-phenyl-1-p-tolylspiro(pyrazole-4¢,3-[1,2,4]-
thiadiazole)-3¢,5¢-dione] (34)
A mixture of anhydrous potassium carbonate (3 gm),
dry dioxane (30 mL), a catalytic amount of tetrabutylam-
monium bromide [TBAB] (0.005 mol), ethylcyanoacetate
(0.005 mol, 0.53 mL) and phenyl isothiocyanate (0.005 mol,
21. Michaelis, A.; Burmeister, R. Ber. 1892, 25, 1502.
22. Musante, C.; Fabbrini, L. Gazz. Chim. Ital. 1954, 84, 593.
23. Kumar, A.; Ila, H.; Junjappa, H. Synthesis 1976, 324.