Reactions with maleimides XI:1 Dipolar cycloaddition reactions with thiazolonylarylhydrazones: A new route for the synthesis of several new thiazolonylpyrazoles of expected biological activities

Article abstract of DOI:10.1080/10426500210665

Several new pyrrolopyrazoles were synthesised via the reaction of thiazolonylarylhydrazones with N-arylmaleimides followed by partial dehydrogenation using bromobenzene and complete aromatization using nitrobenzene. Structures were elucidated by elemental

Full text of DOI:10.1080/10426500210665

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Reactions with Maleimides XI: 1 Dipolar Cycloaddition
Reactions with Thiazolonylarylhydrazones: A
New Route for the Synthesis of Several New
Thiazolonylpyrazoles of Expected Biological Activities
Sanaa M. Eldin a , Hatem M. Gaber a & Sami S. Ghabrial a
a Department of Chemistry of Pesticides , National Research Center and National
Organization for Drug Control and Research , Cairo, Egypt
Published online: 27 Oct 2010.
To cite this article: Sanaa M. Eldin , Hatem M. Gaber & Sami S. Ghabrial (2002) Reactions with Maleimides XI: 1 Dipolar
Cycloaddition Reactions with Thiazolonylarylhydrazones: A New Route for the Synthesis of Several New Thiazolonylpyrazoles
of Expected Biological Activities, Phosphorus, Sulfur, and Silicon and the Related Elements, 177:4, 803-810, DOI:
10.1080/10426500210665
To link to this article: http://dx.doi.org/10.1080/10426500210665
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:803–810
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Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
REACTIONS WITH MALEIMIDES XI:1 DIPOLAR
CYCLOADDITION REACTIONS WITH
THIAZOLONYLARYLHYDRAZONES: A NEW ROUTE
FOR THE SYNTHESIS OF SEVERAL NEW
THIAZOLONYLPYRAZOLES OF EXPECTED
BIOLOGICAL ACTIVITIES
Sanaa M. Eldin, Hatem M. Gaber, and Sami S. Ghabrial
Department of Chemistry of Pesticides, National Research
Center and National Organization for Drug Control
and Research, Cairo, Egypt
(Received July 23, 2001; accepted October 11, 2001)
Several new pyrrolopyrazoles were synthesised via the reaction of thia-
zolonylarylhydrazones with N-arylmaleimides followed by partial de-
hydrogenation using bromobenzene and complete aromatization using
nitrobenzene. Structures were elucidated by elemental analyses and
spectral data studies.
Keywords: Dipolar cycloaddition reactions; N-arylmaleimides; pyrrolo-
pyrazoles; thiazolones
INTRODUCTION
Pyrazoles and annelated pyrazoles have long been known to exhibit
diverse biological activities.1 Among these activities include their
use as CAMP phosphodiesterase inhibitors,2 antipyretic,3 antitumor,4
hypnotic,5 and herbicidal6 agents. Moreover, thiazoles are also reported
to be used in several pharmaceutical and medicinal preparations.7,8 It
was of value to combine the two moieties in a series of derivatives with
the objective of investigating their expected biological activities. The
reactions of thiazolonylarylhydrazones with N-arylmaleimides seemed
to be an easy, logical and unique route for the synthesis of the de-
sired heterocyclic derivatives. This reaction was first reported from this
laboratory.9
Address correspondence to S. M. Eldin, Department of Chemistry of Pesticides, Na-
tional Research Center, Dokki, Giza, Egypt.
803

804
S. M. Eldin et al.
RESULTS AND DISCUSSION
It has been found that the thiosemicarbazones of aromatic aldehydes
1a–1c reacted with chloroacetic acid (2) to give the N-[2-thiazolin-4-on-
2-yl)arylhydrazones 3a–3c which were taken as the starting materials
for the present study (Figure 1). Thus, it was found that 3a reacted
with N-phenylmaleimide (4a) to yield a reaction product of molecular
formula C20H16N4O3S resulting from equimolecular addition of 3a to
4a. The IR spectrum of this reaction product showed the presence of
CO NAr CO,10 NH, a ring-CO, and saturated CH and CH2 groups. Its
1H NMR spectrum revealed the signals at 3.9 (t, pyrrolidine H-3), 4.3
(d, pyrrolidine H-4), 4.9 (d, pyrazolidine H-3), 5.8 (s, thiazolonyl-
CH2), and 4.5 (s, br, NH), in addition to aromatic protons at 7.1–
7.8 (m, 10H). In the light of the above findings, this reaction product
was formulated as the 5-thiazolonylpyrrolidino[3,4-d]pyrazolidine-2,6-
dione derivative 5a (cf. Experimental Part).
FIGURE 1

Cycloaddition Reactions
805
Analogously, 3a reacted with N-p-chlorophenylmaleimide (4b) and
with N-p-methylphenylmaleimide (4c) to give the corresponding
5-thiazolonylpyrrolidino[3,4-d]pyrazolidine-2,6-dione derivatives 5b
and 5c respectively. Structures of 5b, 5c were also established based on
correct elemental analyses and spectral data (cf. Experimental Part).
On the other hand, the arylhydrazone 3b cycloadded to each of
4a–4c to give good yields of the pyrrolidino[3,4-d]pyrazolidine-2,6-dione
derivatives 5d–5f respectively. IR and 1H NMR spectral data, in addi-
tion to elemental analysis, were used for establishment of the structure
of 5d–5f as for 5a–5c respectively cited (cf. Experimental Part).
Moreover, compounds 5g–5i could also be obtained on cycloaddition of
the arylhydrazone derivative 3c to each of the maleimides 4a–4c. Again,
compounds 5g–5i were confirmed by elemental analyses and spectral
data which were in a good agreement with the assigned structures (cf.
Experimental Part).
The course of dehydrogenation of compound 5 was taken as an addi-
tional evidence for their assigned structure. Thus, partial dehydrogena-
tion of 5a–5i using bromobenzene resulted in the formation of products
with two hydrogens less than the corresponding startings 5a–5i in each
case. The absorption band of the NH group was entirely absent in the
1
IR spectra of these reaction products. Moreover, their H NMR spec-
tra did not reveal neither NH nor pyrazolidine H-3 protons in each
case. Based on the above results, these reaction products could be for-
mulated as the 5-thiazolonylpyrrolidino[3,4-d]-12-pyrazoline-2,6-dione
derivatives 6a–6i, respectively (cf. Experimental Part).
On the other hand, complete dehydrogenation of 6a–6i was achieved
via boiling their solutions in nitrobenzene to give the corresponding
5-thiazolonylpyrrolo[3,4-d]pyrazole-2,6-dione derivatives 7a–7i, re-
spectively. 1H NMR spectra of 7a–7i did not reveal any signals of pyrro-
lidine or pyrazolidine or NH protons, thus supporting the assigned
structures. A further proof of the structure of 7a–7i came from their
alternative synthesis via direct dehydrogenation of the corresponding
5a–5i by boiling their solutions in nitrobenzene. Compounds 7a–7i pre-
pared via this route were found completely identical with 7a–7i pre-
pared via the first route (cf. Experimental Part). The biological activity
of 5–7 is now being carried out.
EXPERIMENTAL
All melting points were uncorrected. IR (KBr discs) spectra were
1
recorded on Perkin Elmer FT-IR type 4 spectrophotometer. H NMR
spectra were recorded on Varian Gemini 200 MHz spectrometer in

806
S. M. Eldin et al.
CDCl3 using TMS as an internal standard. Chemical shifts are
expressed as units. Microanalyses were performed at the Microanaly-
tical center of Cairo University. Compounds 311 and 412 were prepared
according to literature procedures.
Synthesis of 5a–5i
A solution of each of 3a–3c (0.01 mmol) in acetic acid (20 mL) was
treated with the appropriate 4a–4c (0.01 mmol), and the reaction mix-
ture was then heated under reflux for 4 h. Removal of the solvent gave
a residue which was crystallized from glacial acetic acid and identified
as 5a–5i respectively (cf. Tables I and II).
TABLE I Characterization Data of the Newly Synthesized Compounds
% Analysis calcd./found
m.p. ( C)
(color)
Yield
(%)
Molecular
formula
Comp.
C
H
N
S
Cl
5a
251-2
Yellow
253-4
Yellow
237-9
P. Yellow
293-4
Yellow
280-1
White
268-9
Yellow
262-3
Yellow
252-3
Yellow
298-9
Yellow
255-6
Yellow
256-7
Yellow
244-6
Yellow
286-7
90
95
97
91
89
88
93
94
92
90
88
81
87
89
C20H16N4O3S
C20H15N4O3SCl
C21H18N4O3S
61.21 4.11 14.27 8.17
61.40 4.30 14.50 8.40
56.27 3.54 13.12 7.51
56.40 3.60 13.40 7.70
62.05 4.46 13.78 7.89
62.30 4.70 13.90 7.70
56.27 3.54 13.12 7.51
56.40 3.70 13.40 7.80
—
—
8.30
8.50
—
—
8.30
8.20
5b
5c
5d
5e
5f
C
20H15N4O3SCl
C20H14N4O3SCl2 52.07 3.06 12.14 6.95 15.37
52.20 3.30 12.40 6.80 15.50
C21H17N4O3SCl
57.20 3.88 12.70 7.27
57.40 3.70 12.50 7.10
59.71 4.26 13.27 7.58
59.90 4.30 13.10 7.40
55.20 3.72 12.26 7.00
55.40 3.90 12.10 7.20
60.55 4.58 12.84 7.33
60.70 4.40 12.60 7.50
61.52 3.61 14.35 8.21
61.70 3.50 14.60 8.00
56.54 3.08 13.18 7.54
56.70 3.30 13.40 7.20
62.36 3.98 13.85 7.92
62.50 3.70 13.60 7.70
56.54 3.08 13.18 7.54
56.80 3.20 13.20 7.70
8.04
8.20
—
5g
5h
5i
C
C
21H18N4O4S
—
21H17N4O4SCl
7.77
7.50
—
—
—
C22H20N4O4S
6a
6b
6c
6d
6e
C
C
C
20H14N4O3S
20H13N4O3SCl
21H16N4O3S
—
8.34
8.10
—
—
8.34
8.50
C20H13N4O3SCl
Yellow
285-6
Yellow
C20H12N4O3SCl2 52.30 2.63 12.20 6.98 15.43
52.10 2.40 12.00 6.80 15.30

Cycloaddition Reactions
807
TABLE I Characterization Data of the Newly Synthesized Compounds
(Continued)
% Analysis calcd./found
m.p. ( C)
(color)
Yield
(%)
Molecular
formula
Comp.
C
H
N
S
Cl
6f
278-9
Yellow
264-5
Yellow
262-4
Yellow
256-7
Yellow
296-8
Brown
258-6
Brown
280-2
Brown
>300
Brown
>300
Brown
>300
Brown
>300
Brown
>300
92
87
92
90
79
85
79
75
80
83
84
80
79
C21H15N4O3SCl
C21H16N4O4S
C21H15N4O4SCl
C22H18N4O4S
57.47 3.44 12.76 7.30
57.70 3.70 12.50 7.10
60.00 3.80 13.33 7.61
60.20 4.00 13.20 7.80
55.44 3.30 12.32 7.04
55.20 3.50 12.20 6.80
60.82 4.14 12.90 7.37
61.10 4.30 12.70 7.20
61.84 3.11 14.42 8.25
61.60 3.40 14.20 8.40
56.81 2.62 13.25 7.58
56.70 2.80 13.40 7.70
62.67 3.50 13.92 7.96
62.90 3.20 14.10 7.70
56.81 2.62 13.25 7.58
56.60 2.90 13.50 7.40
8.07
8.30
—
6g
6h
6i
—
7.81
8.00
—
—
—
7a
7b
7c
7d
7e
7f
C
20H12N4O3S
—
C20H11N4O3SCl
8.38
8.20
—
—
8.38
8.10
C21H14N4O3S
C20H11N4O3SCl
C20H10N4O3SCl2 52.53 2.20 12.25 7.01 15.50
52.70 2.50 12.40 7.30 15.20
C21H13N4O3SCl
C21H14N4O4S
57.73 3.00 12.82 7.34
57.60 3.30 13.00 6.70
60.28 3.34 13.39 7.65
60.40 3.50 13.20 7.40
55.69 2.87 12.37 7.07
55.50 2.70 12.20 7.20
61.11 3.70 12.96 7.40
61.30 3.90 13.10 7.20
8.11
8.40
—
7g
7h
7i
—
C21H13N4O4SCl
7.84
7.70
—
Brown
>300
Brown
C22H16N4O4S
—
Partial Dehydrogenation of 5a–5i
A solution of each of 5a–5i (1.0 g) in bromobenzene (15 mL) was heated
under reflux for 3 h. Removal of the solvent left behind a residue which
was crystallized from glacial acetic acid and identified as 6a–6i, respec-
tively (cf. Tables I and II).
Complete Dehydrogenation of 5a–5i or 6a–6i
A solution of each of 5a–5i or 6a–6i in nitrobenzene (15 mL) was heated
under reflux for 3 h. The solvent was steam-distilled, and the residue
obtained was triturated several times with cold ethanol. Crystallization
from ethanol gave 7a–7i respectively (cf. Tables I and II).

808
S. M. Eldin et al.
TABLE II IR and 1H NMR Data of the Synthesized Compounds
1
Comp.
IR [KBr, cm
]
1H NMR [CDCl3/ ]
5a
3300 (NH); 2980 (sat. CH and CH2);
1780,1710 (CONArCO) and
1680 (ring-CO)
3.9 (t, 1H, pyrrolidine H-3); 4.3 (d,
1H, pyrrolidine H-4); 4.5 (s, br,
1H, NH); 4.9 (d, 1H, pyrrolidine
H-3); 5.8 (s, 2H, thiazolonyl-CH2)
and 7.1–7.8 (m, 10H, ArH’S)
5b
5c
3330 (NH); 2985 (sat. CH and CH2);
1770,1700 (CONArCO) and
1670 (ring-CO)
3350 (NH); 2975 (sat. CH and CH2);
1780,1700 (CONArCO) and
1680 (ring-CO)
1.6 (s, 3H, CH3); 3.92 (t, 1H,
pyrrolidine H-3); 4.25 (d, 1H,
pyrrolidine H-4); 4.7 (s, br, 1H,
NH); 4.95 (d, 1H, pyrrolidine
H-3); 5.9 (s, 2H, thiazolonyl-CH2)
and 7.1–7.7 (m, 9H, ArH’S)
5d
5e
5f
3300 (NH); 2980 (sat. CH and CH2);
1770,1720 (CONArCO) and
1680 (ring-CO)
3350 (NH); 2985 (sat. CH and CH2);
1770,1715 (CONArCO) and
1680 (ring-CO)
3330 (NH); 2975 (sat. CH and CH2);
1770,1710 (CONArCO) and
1675 (ring-CO)
5g
3300 (NH); 2975 (sat. CH and CH2);
1770,1710 (CONArCO) and
1675 (ring-CO)
3.8 (s, 3H, OCH3); 3.95 (t, 1H,
pyrrolidine H-3); 4.3 (d, 1H,
pyrrolidine H-4); 4.85 (s, br, 1H,
NH); 5.1 (d, 1H, pyrrolidine H-3);
5.85 (s, 2H, thiazolonyl-CH2)
and 7.1–7.6 (m, 9H, ArH’S).
5h
5i
3350 (NH); 2980 (sat. CH and CH2);
1770,1710 (CONArCO) and
1680 (ring-CO)
3330 (NH); 2980 (sat. CH and CH2);
1780,1715 (CONArCO) and
1680 (ring-CO)
1.59 (s, 3H, CH3); 3.0 (S, 3H, OCH3);
3.7 (t, 1H, pyrrolidine H-3); 4.25
(d, 1H, pyrrolidine H-4); 4.82 (s,
br, 1H, NH); 4.92 (d, 1H,
pyrrolidine H-3); 5.8 (s, 2H,
thiazolonyl-CH2) and 7.1–7.7
(m, 8H, ArH’S)
6a
6b
6c
2980 (sat. CH and CH2); 1770,1710
(CONArCO) and 1680 (ring-CO)
2985 (sat. CH and CH2); 1780,1715
(CONArCO) and 1685 (ring-CO)
2980 (sat. CH and CH2); 1770,1700
(CONArCO) and 1670 (ring-CO)
1.6 (s, 3H, CH3); 3.95 (d, 1H,
pyrrolidine H-3); 4.7 (d, 1H,
pyrrolidine H-4); 5.8 (s, 2H,
thiazolonyl-CH2) and 7.0–7.7
(m, 9H, ArH’S)

Cycloaddition Reactions
809
TABLE II IR and 1H NMR Data of the Synthesized Compounds (Continued)
1
Comp.
IR [KBr, cm
]
1H NMR [CDCl3/ ]
6d
2985 (sat. CH and CH2); 1775,1705
(CONArCO) and 1670 (ring-CO)
2980 (sat. CH and CH2); 1770,1705
(CONArCO) and 1680 (ring-CO)
2980 (sat. CH and CH2); 1770,1710
(CONArCO) and 1675 (ring-CO)
6e
6f
1.55 (s, 3H, CH3); 3.85 (d, 1H,
pyrrolidine H-3); 4.8 (d, 1H,
pyrrolidine H-4); 5.82 (s, 2H,
thiazolonyl-CH2) and 7.0–7.7
(m, 8H, ArH’S)
6g
6h
6i
2980 (sat. CH and CH2); 1780,1710
(CONArCO) and 1680 (ring-CO)
2985 (sat. CH and CH2); 1770,1705
(CONArCO) and 1670 (ring-CO)
2980 (sat. CH and CH2); 1780,1710
(CONArCO) and 1675 (ring-CO)
2980 (sat. CH2); 1770,1710 (CONArCO)
and 1680 (ring-CO)
2985 (sat. CH2); 1780,1705 (CONArCO)
and 1675 (ring-CO)
2980 (sat. CH2); 1770,1710 (CONArCO)
and 1685 (ring-CO)
7a
7b
7c
5.8 (s, 2H, thiazolonyl-CH2) and
7.0–7.6 (m, 10H, ArH’s)
1.62 (s, 3H, CH3); 5.82 (s, 2H,
thiazolonyl-CH2) and 7.1–7.7
(m, 9H, ArH’s)
7d
7e
7f
2985 (sat. CH2); 1750,1700 (CONArCO)
and 1675 (ring-CO)
2975 (sat. CH2); 1770,1705 (CONArCO)
and 1670 (ring-CO)
2980 (sat. CH2); 1775,1710 (CONArCO)
and 1675 (ring-CO)
1.58 (s, 3H, CH3); 5.9 (s, 2H,
thiazolonyl-CH2) and 7.0–7.6
(m, 8H, ArH’s)
7g
7h
7i
2985 (sat. CH2); 1780,1715 (CONArCO)
and 1680 (ring-CO)
2985 (sat. CH2); 1770,1705 (CONArCO)
and 1675 (ring-CO)
2990 (sat. CH2); 1770,1705 (CONArCO)
and 1680 (ring-CO)
1.52 (s, 3H, CH3); 3.8 (s, 3H, OCH3);
5.9 (s, 2H, thiazolonyl-CH2) and
6.9–7.7 (m, 8H, ArH’s)
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