γ-oxo carboxylic acids in heterocyclic synthesis, III. Synthesis of biologically active 4-benzylamino-6-(5,5-dioxodibenzothiophen-2-yl)-2,3,4,5- tetrahydropyridazin-3-ones

Article abstract of DOI:10.1515/znb-2002-0613

α-Benzylamino-β-(5,5-dioxodibenzothiophen-2-carbonyl)propionic acid (1) has been synthesized by treating the corresponding β-aroylacrylic acid with benzylamine in dry benzene. On treatment with hydrazine hydrate the keto acid 1 furnishes the corresponding pyridazinone derivative 2. The behaviour of 2 towards carbon electrophiles, namely, ethyl chloroacetate, acrylonitrile, formaldehyde and secondary amines (under Mannich reaction conditions), aromatic aldehydes and carbon nucleophiles, namely, POCl₃/PCl₃ and P₂S₅ has been investigated. The 3-chloropyridazine derivative 13 reacts with hydrazine hydrate to give the 3-hydrazino derivative 14. On treatment with ethyl acetoacetate and/or acetylacetone the hydrazine 14 undergoes cyclization to afford pyrazolone derivative 16 and 3-(3,5-dimethylpyrazol-1-yl)pyridazine derivative 17, respectively. On reaction with acetylhydrazine in boiling butanol and/or sodium azide in DMF the 3-chloropyridazine derivative 13 affords the triazolo[4,3-b]pyridazine 18 and the tetrazolo[1,5-b]pyridazine 19, respectively. The anti-microbial activity of the synthesized derivatives has been investigated.

Full text of DOI:10.1515/znb-2002-0613

γ-Oxo Carboxylic Acids in Heterocyclic Synthesis, III.
Synthesis of Biologically Active 4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-2,3,4,5-tetrahydropyridazin-3-ones
Ashraf A. F. Wasfy, Mohamed M. H. Arief, Mahassen S. Amine, Shafey G. Donia,
and Aly A. Aly
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Reprint requests to Dr. A. A. F. Wasfy
Z. Naturforsch. 57b, 668Ð676 (2002); received August 13, 2001
Heterocyclic Synthesis
α-Benzylamino-ꢀ-(5,5-dioxodibenzothiophen-2-carbonyl)propionic acid (1) has been syn-
thesized by treating the corresponding ꢀ-aroylacrylic acid with benzylamine in dry benzene.
On treatment with hydrazine hydrate the keto acid 1 furnishes the corresponding pyridazi-
none derivative 2. The behaviour of 2 towards carbon electrophiles, namely, ethyl chloroace-
tate, acrylonitrile, formaldehyde and secondary amines (under Mannich reaction conditions),
aromatic aldehydes and carbon nucleophiles, namely, POCl3/PCl3 and P2S5 has been investi-
gated. The 3-chloropyridazine derivative 13 reacts with hydrazine hydrate to give the
3-hydrazino derivative 14. On treatment with ethyl acetoacetate and/or acetylacetone the
hydrazine 14 undergoes cyclization to afford pyrazolone derivative 16 and 3-(3,5-dimethyl-
pyrazol-1-yl)pyridazine derivative 17, respectively. On reaction with acetylhydrazine in boil-
ing butanol and/or sodium azide in DMF the 3-chloropyridazine derivative 13 affords the
triazolo[4,3-b]pyridazine 18 and the tetrazolo[1,5-b]pyridazine 19, respectively. The anti-mi-
crobial activity of the synthesized derivatives has been investigated.
A review (in two parts) on the pharmacological synthesize a new series of pyridazine derivatives,
activity of pyridazine derivatives has been pub- with the objective of obtaining new biologically
lished [1, 2]. They include analgesic, antiinflamma- active compounds.
tory, antisecretory, antiulcer agents, antidepres-
The various steps involved in the synthesis of
sants, neuroleptics, anxiolytics, sedative-hypnotics, the title compound 2 and its reaction with a variety
tranquillizers, anti-convulsants, GABA antago- of reagents are shown in Schemes 1 and 2.
nists, blood platelet aggregation inhibitors and
The required α-benzylamino-ꢀ-(5,5-dioxodiben-
antithrombotics, antitumor agents, immunosup- zothiophen-2-carbonyl)propionic acid (1) was syn-
pressant agents, cardiotonics, coronary vasodilata- thesized from the corresponding ꢀ-(5,5-dioxo-
tors, antiarrhythmics, cardioselective ꢀ-blockers, dibenzothiophen-2-carbonyl)acrylic
antihypertensive, antihypotensive and hypocholes- benzylamine in dry benzene under Michael reac-
terolaemic agents. tion conditions. The condensation of 1 with hydra-
acid
and
α,ꢀ-Unsaturated γ-oxo acids are of limited use zine hydrate in boiling ethanol furnished the cor-
since the unsaturated acids are difficult to obtain. responding 4-benzylamino-6-(5,5-dioxodibenzo-
Most frequently used are mucic acid and its deriv- thiophen-2-yl)-2,3,4,5-tetrahydropyridazin-3-one
atives, which produce 4,5-dihalopyridazines from (2).
2,3-dichloro-4-oxobut-2-enoic acid [3] or 2,3-di-
Reactivity of 2, which bears bulkyheteryl moie-
bromo-4-oxobut-2-enoic acid [4]. Several pyridazi- ties at position 4 and 6 and the effects of steric
nones have been obtained by pyrolytic decomposi- hinderance of these groups have been studied with
tion of semicarbazones of 4-oxo acids [5] or different carbon electrophiles and nitrogen nu-
hydrazones of unsaturated 4-oxo acids [6]. cleophiles. Thus, pyridazinone 2 reacted with ethyl
Prompted by these observations and in continua- chloroacetate in boiling dry acetone and dry
tion of our studies on the utilization of α,ꢀ-unsatu- K2CO3 to afford 4-benzylamino-3-o-carboethoxy-
rated γ-oxo acids in the synthesis of diazine het- methyl-6-(5,5-dioxodibenzothiophen-2-yl)-4,5-
erocycles [7Ð9], we thought it worthwile to dihydropyridazine (3). Alkaline hydrolysis of the
0932Ð0776/2002/0600Ð0668 $06.00 ” 2002 Verlag der Zeitschrift für Naturforschung, Tübingen · www.znaturforsch.com
D
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A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
669
ester 3 followed by acidification yielded the 4- 3-(2H)-one was studied. Thus, on treatment of 2
benzylamino-3-o-carboxymethyl-6-(5,5-dioxo- with acrylonitrile in boiling ethanol containing ca-
dibenzothiophen-2-yl)-4,5-dihydropyridazine (4) talytic amounts of aqueous sodium hydroxide so-
which upon subsequent dehydration with poly- lution, a Michael-type addition occurred at the ac-
phosphoric acid furnished the 1-benzyl-7-(5,5-di- tivated double bond and afforded the 4-
oxodibenzothiophen-2-yl)-2-oxomorpholino-[3,4-b]- benzylamino-2-cyanoethyl-6-(5,5-dioxodibenzo-
2,3,8,8a-tetrahydropyridazine (5). The reactivity of thiophen-2-yl)-4,5-dihydropyridazin-3-one (6).
2 towards some reagents which are known to at-
On the other hand, compound 2 reacted readily
tack the nitrogen atom at position 2 of pyridazin- with formaldehyde in boiling ethanol to give the
Scheme 1.
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670
A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
2-hydroxymethyl derivative 7 which on cyclocon- 3-[1N-(3-methylpyrazolin-5-one)]-4,5-dihydro-
densation with urea yielded 9-benzylamino-7-(5,5- pyridazine (16). With acetylacetone 14 cyclized to
dioxodibenzothiophen-2-yl)-2,3,4,8,9-pentahydro-
pyridazino[1,6-a]-1,3,5-triazin-2-one (8). When 2
was allowed to react with formaldehyde and sec-
ondary amines, namely, piperidine and/or morpho-
line in ethanol, we obtained the Mannich bases
9a,b, respectively. The same bases were obtained
when the corresponding hydroxymethyl derivative
7 was treated with piperidine and/or morpholine.
Base catalysed condensation of 2 with aromatic
aldehydes, namely, benzaldehyde and/or p-chloro-
benzaldehyde afforded the corresponding 5-aryl-
idene-4-benzylamino-6-(5,5-dioxodibenzothio-
phen-2-yl)-2,3,4-trihydropyridazin-3-one (10a,b).
Sometimes the incorporation of amino acid resi-
dues in various sulfur- and nitrogen-containing
heterocycles enhances the biological profile many-
fold over that of its parent nucleus [10Ð12]. Due
to the interest in this class of compounds we have
previously reported the synthesis and biological
evaluation of 2-N-(pht- or tos-aminoacyl)mer-
capto- or amino-pyrimidine derivatives [13]. In
continuation, we considered to synthesize novel
congeners bearing pyridazine and amino acid
moieties in a single molecular framwork likely to
constitute potent antimicrobial agents. Thus, com-
pound 2 reacted with phthalyl and/or tosyl deriva-
tives of the amino acids glycine and/or DL-alanine
to furnish 4-benzylamino-6-(5,5-dioxodibenzothio-
phen-2-yl)-3-o-(pht- or tos-amino acid)-4,5-dihy-
dropyridazine derivatives (11, 12)a,b, respectively.
In an attempt to prepare biologically active
compounds from pyridazine derivatives, the utili-
zation of hydrazinopyridazine derivatives [14] has
been also investigated. Thus, on treatment with
POCl3ÐPCl5 4-benzylamino-6-(5,5-dioxodibenzo-
thiophen-2-yl)-2,3,4,5-tetrahydropyridazin-3-one
Scheme 2.
(2) gave 3-chloropyridazine derivative 13 which
was subsequently converted into the 3-hydrazino- 4-benzylamino-3-(3,5-dimethylpyrazol-1-yl)-6-
pyridazine derivative 14 by treatment with hydra- (5,5-dioxodibenzothiophen-2-yl)-4,5-dihydro-
zine hydrate in refluxing ethanol. Interestingly, the pyridazine (17). On the other hand, refluxing of
structure of compound 14 was established chemi- 14 with acetic acid produced the corresponding
cally by independent synthesis via the reaction of 8-benzylamino-6-(5,5-dioxodibenzothiophen-2-yl)-
2 with phosphorus pentasulphide in boiling xylene. 1,2,4-triazolo[4,3-b]-7,8-dihydropyridazine
(18).
Upon subsequent reaction with hydrazine hydrate Compound 18 was also obtained by an independ-
The 3-mercaptopyridazine derivative 15 yielded ent synthesis via the condensation of 13 with ace-
the 3-hydrazino derivative 14. Reaction of 14 with tylhydrazine in boiling n-butanol. Further, the re-
ethyl acetoacetate in boiling ethanol produced 4- action of 14 with a mixture of sodium nitrite and
benzylamino-6-(5,5-dioxodibenzothiophen-2-yl)-
conc. HCl afforded the 8-benzylamino-6-(5,5-di-
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A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
671
oxodibenzothiophen-2-yl)-1,2,3,4-tetrazolo[1,5-b]-
Table 1: Activity (A) and minimum inhibitory concentration (MIC) calculated as mmol/ml for compound 2bÐ7b.
Comp. Bacillus subtilis
Aa MICb
Bacillus cereus
Escherichia coli
Aspergillus niger
Penicillium notatum
A
MIC
A
MIC
A
MIC
A
MIC
2
6
+++ 1.2 ¥ 10Ð3
++
++
++
6.0 ¥ 10Ð4
5.3 ¥ 10Ð4
1.1 ¥ 10Ð3
++
++
++
++
++
++
++
3.0 ¥ 10Ð4
2.7 ¥ 10Ð4
5.6 ¥ 10Ð4
4.8 ¥ 10Ð4
2.1 ¥ 10Ð4
5.1 ¥ 10Ð4
2.8 ¥ 10Ð4
++
++
++
++
++
++
++
6.0 ¥ 10Ð4
5.3 ¥ 10Ð4
5.6 ¥ 10Ð4
2.4 ¥ 10Ð4
4.1 ¥ 10Ð4
5.1 ¥ 10Ð4
2.8 ¥ 10Ð4
++
++
++
3.0 ¥ 10Ð4
5.3 ¥ 10Ð4
1.1 ¥ 10Ð3
+
2.7 ¥ 10Ð4
2.8 ¥ 10Ð4
2.4 ¥ 10Ð4
4.1 ¥ 10Ð4
7
++
+
++
9b
11a
17
19
+++ 9.7 ¥ 10Ð4
+++ 9.7 ¥ 10Ð4
++
++
++
4.1 ¥ 10Ð4
2.5 ¥ 10Ð4
5.7 ¥ 10Ð4
++
++
++
4.1 ¥ 10Ð4
2.5 ¥ 10Ð4
5.7 ¥ 10Ð4
+++ 1.0 ¥ 10Ð3
++
5.7 ¥ 10Ð4
a The width of the zone of inhibition indicates the potency of antimicrobial activity.
(Ð) no antimicrobial activity; (+) weak activity with the diameter of the zone equal to 0.7 cm;
(++) moderate activity with the diameter of the zone equal to 1.3 cm; (+++) marked activity with
the diameter of the zone equal to 1.7 cm; b origin of cultures.
Botany Department, Faculty of Science, Benha University, Egypt.
The results of the control samples were not included in the Table; they show negative responses.
Experimental Section
7,8-dihydropyridazine (19). Compound 19 was
also obtained via reaction of 13 with sodium azide.
The structures of the above compounds were
Melting points were taken in open capillary
tubes and are uncorrected. IR spectra in KBr were
confirmed from their physical and analytical data recorded on a Pye-Unicam Sp-1200 spectropho-
tometer and 1H-NMR spectra in DMSO on a
(Table 2) and from their spectral data (Table 3).
JOEl Fx 90 Q9 MHz (Fourier transform NMR
spectrometer) using TMS as internal reference
Screening for Antimicrobial Activity
(chemical shifts are expressed as δ, ppm). Mass
The antimicrobial activities of our compounds
were determined in vitro by the filter paper disc
spectra were recorded on an HP Model MS 5988
spectrometer and microanalytical data were ob-
method [14]. All compounds were tested for activ- tained from the Microanalytical Center at Cairo
University.
ity against Gram-positive, Gram-negative bacteria,
and selected fungi.
α-Benzylamino-ꢀ-(5,5-dioxodibenzothiophen-
2-carbonyl)propionic acid (1)
The culture medium was normal nutrient agar
(NA) supplemented with 1 g of yeast per ml. Ac-
cording to the solubility of the tested compounds,
different polar and nonpolar solvents were used,
and a good solubility was shown in 10% acetone
(v/v) for all test compounds. Based on the previous
preliminary test, closely spaced test concentrations
(500, 250, 125 µg/ml) were selected. A qualitative
screen was performed on all compounds while
quantitative assays were done on active com-
pounds only. The results are summarized in Ta-
ble 1. Only 2, 9b and 17 were found to possess
marked activity at a minimal inhibitory concentra-
tion (MIC) of (500 µg/ml) against Bacillus subtilis,
Bacillus cereus and Penicillium notatum; these
A mixture of ꢀ-aroylacrylic acid (15 g, 0.047
mol) and benzylamine (7.49 g, 0.07 mol) in dry
benzene (150 ml) was heated under reflux for 3 h.
The resulting solid formed after concentration and
cooling was crystallized from an appropriate
solvent to give compound 1.
4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-2,3,4,5-tetrahydropyridazin-3-one (2)
A boiling solution of the keto acid 1 (14.8 g,
0.035 mol) in ethanol (150 ml) was treated with
hydrazine hydrate (1.85 g, 0.037 mol). The reac-
tion mixture was refluxed 6 h and the product sep-
arated after concentration was crystallized from a
compounds also showed weak activity at (MIC) of suitable solvent giving the corresponding pyridazi-
none 2.
(250 µg/ml) against Escherichia coli and Aspergil-
lus niger. All other compounds showed very weak
activity against the different strains of bacteria
and fungi.
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672
A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
Table 2: Analytical data.
Comp.
M.p.a [∞C]
Yield [%]
Mol. formula
[mol. wt.]
Calcd. (found) [%]
H
C
N
1
2
268 Ð70
216Ð8
212Ð4
236Ð8
182Ð3
210Ð2
200Ð2
164Ð6
232Ð4
191Ð3
131Ð2
150Ð2
213Ð5
220Ð2
191Ð3
223Ð5
192Ð4
228Ð30
160 Ð2
240Ð2
226Ð8
238Ð40
203Ð5
75
83
85
75
63
70
81
75
71
67
69
71
72
80
81
78
82
92
72
84
83
81
77
C23H19NO5S
(421)
65.55
(65.45
66.18
(66.52
64.41
(64.23
63.15
(63.34
65.64
(65.44
66.38
(66.60
64.42
(64.64
63.69
(63.92
67.70
(67.53
65.11
(65.36
71.28
(71.53
66.72
(66.92
65.56
(65.81
66.01
(66.28
61.14
(61.34
61.68
(61.82
63.37
(63.64
64.03
(64.21
63.74
(63.83
65.19
(65.42
67.87
(67.70
65.93
(65.82
62.44
(62.53
4.51
4.30
4.55
4.71
4.97
5.24
4.42
4.62
4.15
4.53
4.68
4.92
4.69
4.85
4.45
4.34
5.83
5.72
5.42
5.54
4.55
4.80
4.07
4.30
3.97
4.20
4.20
4.44
4.45
4.73
4.67
4.93
4.13
4.38
4.87
4.70
4.38
4.62
4.62
4.94
5.05
5.34
4.61
4.90
4.07
3.98
3.32
3.42)
10.07
10.32)
8.34
C23H19N3O3 S
(417)
3
C27H25N3O5S
(503)
8.55)
8.84
9.05)
9.19
9.32)
11.91
11.71)
9.39
4
C25H21N3 O5S
(475)
5
C25H19N3O4S
(457)
6
C26H22N4O3S
(470)
7
C24H21N3O4S
(447)
9.66)
14.86
14.70)
10.89
10.82)
10.85
10.71)
8.31
8
C25H21N5O3S
(471)
9a
9b
10a
10b
11a
11b
12a
12b
13
14
15
16
17
18
19
C29H30N4O3S
(514)
C28H28N4O4S
(516)
C30H23N3O3S
(505)
8.51)
7.78
C30H22 ClN3O3S
(539.5)
7.60)
9.27
C33H24N4O6S
(604)
C34H26N4O6S
(618)
C32H28N4O6S2
(628)
C33H30N4O6S2
(642)
9.52)
9.06
9.35)
8.91
9.04)
8.72
8.91)
9.64
C23H18 ClN3O2S
(435.5)
9.80)
16.24
16.42)
9.69
C23H21N5O2S
(431)
C23H19N3O2S2
(433)
9.91)
14.08
14.45)
14.14
14.37)
15.38
15.64)
19.00
19.12)
C27H23N5O3S
(497)
C28H25N5O2S
(495)
C25H21N5O2S
(455)
C23H18N6O2S
(442)
a All compounds were recrystallized from ethanol except for 1, 3, 14 and 18 which were recrystallized from benzene.
4-Benzylamino-3-o-carboethoxymethyl-6-
(5,5-dioxodibenzothiophen-2-yl)-4,5-dihydro-
pyridazine (3)
was removed by distillation and the reaction mix-
ture then poured into water and the organic
material was extracted with ether. After evapoura-
tion of the dried ethereal solution, the solid that
separated was crystallized from a suitable solvent
to afford the corresponding ester 3.
A mixture of pyridazinone 2 (1.8 g, 0.004 mol),
anhydrous K2CO3 (2.20 g, 0.016 mol), ethyl chlo-
roacetate (1.96 g, 0.016 mol) and dry acetone
(50 ml) was refluxed for 35 h. The excess acetone
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A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
Table 3: Spectral data of compounds 1Ð19.
673
Comp.
IR (KBr) [cmÐ1
]
1H-NMR (DMSO) δ/ppma
MS (70 eV) m/z [%]
1
3470Ð3200 (OH and NH),
1715 (carboxylic CO), 1675
(ketonic CO), 1625 (C=C),
1330 and 1160 (S=O)
2.6Ð3.3 (m, with interference, 4H, non-equiva- 421(M+, 4.18), 216 (100)
lent CH2 and CH2Ph), 4.1 (q, 1H, methine),
5.7 (br s, 1H, acyclic NH), 6.8Ð7.6 (m, 12H,
ArH), 11.5 (s, 1H, OH)
2
3
3450Ð3170 (OH and NH),
2.7Ð3.4 (m, with interference, 4H, non-equiva- 417 (M+, 3.41), 91 (100)
1675Ð1660 (amidic CO), 1620 lent CH2 and CH2Ph), 3.8 (q, 1H, methine),
(C=C), 1595 (C=N), 1340 and 5.5 (br s, 1H, acyclic NH), 6.7Ð7.8 (m, 12H,
1150 (S=O)
ArH), 8.9 (br s, 1H, cyclic NH)
3300Ð3200 (NH), 1735 (CO
ester), 1628 (C=C), 1605
(C=N), 1350 and 1140
(S=O)
1.2 (t, J =7.1 Hz, 3H, ester CH ), 2.7Ð3.4 (m, 503 (M+, 4.66), 77 (100)
3
with interference, 4H, non-equivalent CH2 and
CH2Ph), 3.7 (q, J =7.1 Hz, 2H, ester CH ), 4.0
2
(q, 1H, methine), 4.6 (s,2H, OCH2), 5.9 (br s,
1H, acyclic NH), 6.8Ð7.9 (m, 12 H, ArH)
5
6
1680 (amidic CO), 1618
(C=C), 1607 ( C=N), 1350
and 1140 (S=O)
3330Ð3190 (NH), 2240
(CϵN),1670 (amidic CO),
1626 (C=C), 1610 (C=N),
1370 and 1145 (S=O)
2.6Ð3.4 (m, with interference, 4H, non-equiva- 457 (M+, 0.82), 216 (100)
lent CH2 and CH2Ph), 3.8 (q, 1H, methine), 4.9
(s, 2H, OCH2CO), 6.8 Ð7.9 (m, 12H, ArH)
2.1 (t, J =7.2 Hz, 2H, NCH ), 2.7Ð3.4 (m,
472(M++2,3.19), 470 (M+,
2
with interference, 4H, non-equivalent CH2 and 5.32), 51 (100)
CH2Ph), 3.6 (t, J =7.2 Hz, 2H, CH CN), 4.0
2
(q, 1H, methine), 5.7 (br s, 1H, acyclic NH),
6.7Ð7.8 (m, 12H, ArH)
7
3440Ð3210 (OH and NH),
2.7Ð3.7 (m, with interference , 6H, non-equiva- 447 (M+, 0.42), 216 (100)
lent CH2, CH2Ph and NCH2), 4.0 (q, 1H, meth-
1668 (amidic CO), 1625
(C=C), 1608 (C=N), 1355 and ine ), 5.8 (br s, 1H, acyclic NH), 6.8Ð7.8 (m,
1140 (S=O)
12H, ArH ), 11.5 (s, 1H, OH)
8
3300Ð3170 (NH), 1675
(amidic CO), 1624 (C=C),
1590 (C=N), 1360 and 1130
(S=O)
2.6Ð3.5 (m, with interference, 4H, non-equiva- 471 ( M+, 2.84), 91 (100)
lent CH2 and CH2Ph), 3.9 (q, 1H, methine), 4.9
(s, 2H, NCH2N), 5.8 (br s, 1H, acyclic NH), 6.7Ð
7.8 (m, 12H, ArH), 8.8 (br s, 1H, cyclic NH)
10a
11b
3450Ð3150 (OH and NH),
1670 (amidic CO), 1630
3.1 (s, 2H, CH2Ph), 4.0 (s, 1H, methine), 5.5
(br s, 1H, acyclic NH), 6.4 (s, 1H, ylidenic H),
505 (M+, 5.88), 77 (100)
(C=C), 1585 (C=N), 1370 and 6.8Ð7.9 (m, 17 H, ArH), 8.9 (br s, 1H, cyclic
1180 (S=O)
3340Ð3170 (NH), 2950Ð2840 1.6 (d, 3H, CH3), 2.5Ð3.3 (m, with interference, 618 (M+, 3.41), 185 (100)
(aliphatic CH), 1780Ð1735 4H, non-equivalent CH2 and CH2Ph), 3.9 (q,
NH)
(imidic CO), 1725 (CO ester), 1H, methine), 4.5 (q, 1H, NCHCO), 5.6 (br s,
1619 (C=C), 1580 (C=N),
1450 and 1120 (S=O)
3310Ð3170 (NHNH2 and
NH), 1625 (C=C), 1610
(C=N), 1380 and 1130
(S=O)
1H, acyclic NH), 6.8Ð7.9 (m, 16 H, ArH)
14
16
2.6Ð3.4 (m, with interference, 4H, non-equiva- 431 ( M+ , 1.84), 79 (100)
lent CH2 and CH2Ph ), 3.9 (q, 1H, methine),
5.5 (br s, 1H, acyclic NH), 6.2 (br s, 2H, NH2)
6.9Ð7.9 (m, 12 H, ArH), 9.2 (br s, 1H,
NHNH2)
3320Ð3180 (NH), 2960Ð2830 2.5Ð3.5 (m, with interference, 7H, non-equiva- 497 ( M+, 2.64), 77 (100)
(aliphatic CH), 1675 (amidic
CO), 1630 (C=C), 1605
lent CH2, CH2Ph and CH3), 4.0Ð4.5 (m, with
interference, 3H, methine and pyrazolone pro-
(C=N), 1350 and 1100 (S=O) tons), 5.6 (br s, 1H, acyclic NH), 6.8Ð7.9 (m,
12H, ArH)
17
18
19
3310Ð3140 (NH), 1625 (C=2.3 (s, 6H, 2
¥CH3), 2.6Ð3.4 (m, with interfer-
495 (M+ , 1.61), 69 (100)
455 (M+, 3.23), 57 (100)
O), 1590 (C=N), 1410 and
1165 (S=O)
ence , 4H, non-equivalent CH2 and CH2Ph),
3.9 (q, 1H, methine ), 5.7 (br s , 1H, acyclic
NH), 6.8Ð7.9 (m, 12H, ArH)
3360Ð3205 (NH), 1618
2.5Ð3.3 (m, with interference, 7H, CH3, non-
(C=C), 1594 (C=N), 1370 and equivalent CH2 and CH2Ph), 4.0 (q, 1H, meth-
1133 (S=O)
ine), 5.5 (br s , 1H, acyclic NH), 6.8Ð7.8 (m,
12H, ArH)
3200Ð3150 (NH), 1620
2.5Ð3.3(m, with interference, 4H, non-equiva- 442 (M+, 0.96), 109 (100)
(C=C), 1595 (C=N), 1420 and lent CH2 and CH2Ph), 4.1 (q, 1H, methine),
1170 (S=O), 1090Ð1050 (tetra- 5.4 (br s, 1H, acyclic NH), 6.8Ð7.8 (m, 12H,
zole ring)8.
ArH)
a All NH signals were exchangeable with D2O oxide.
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674
A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
4-Benzylamino-3-o-carboxymethyl-6-
(5,5-dioxodibenzothiophen-2-yl)-4,5-dihydro-
pyridazine (4)
and triturated with ethanol. The solid obtained
was crystallized from a suitable solvent to give 8.
4-Benzylamino-2-(piperidyl- or morpholino-
methyl)-6-(5,5-dioxodibenzothiophen-2-yl)-4,5-
dihydropyridazin-3-ones (9a,b)
The ester 3 (1.4 g, 0.0028 mol) was added to a
solution containing NaOH (0.44 g, 0.011 mol) dis-
solved in a mixture of ethanol (20 ml) and water
(30 ml). The mixture was refluxed for 5 h. The al-
kaline solution was acidified with ice-cold diluted
HCl and extracted with ether. The solid separated
after evapouration of the dried ethereal layer was
crystallized from a proper solvent to yield the cor-
responding acid 4.
A mixture of pyridazinone 2 (0.75 g, 0.0018
mol), formaldehyde (0.81 g, 0.027 mol) and sec-
ondary amines, namely, piperidine and/or morpho-
line (0.17 g, 0.002 mol) in ethanol (30 ml) was left
overnight at room temperature and then heated
under reflux for 3 h. The solid which formed after
removal of most of the solvent was crystallized
from a suitable solvent to afford 9a,b as colourless
crystals (see Table 2).
1-Benzyl-7-(5,5-dioxodibenzothiophen-2-yl)-
2-oxomorpholino[3,4-b]-2,3,8,8a-tetrahydro-
pyridazine (5)
Independent synthesis of Mannich bases (9a,b)
A mixture of acid 4 (0.71 g, 0.0015 mol) and 20 g
of polyphosphoric acid was kept at 120 ∞C with
stirring for 1 h, the mixture was cooled, 100 g of
ice was added and the isolated product was crys-
tallized from a proper solvent to furnish 5.
A mixture of 2-hydroxymethylpyridazinone 7
(0.5 g, 0.001 mol) and secondary amines, namely,
piperidine and/or morpholine (0.1 g, 0.0012 mol)
in ethanol (25 ml) was heated under reflux for 3 h.
The solid that separated after concentration and
cooling was crystallized from a proper solvent to
yield a product identified to be 9a,b by mp and
mmp determination.
4-Benzylamino-2-cyanoethyl-6-(5,5-dioxodibenzo-
thiophen-2-yl)-4,5-dihydropyridazin-3-one (6)
5-Arylidene-4-benzylamino-6-(5,5-dioxodibenzo-
thiophen-2-yl)-2,3,4-trihydropyridazin-3-one (10a,b)
A mixture of pyridazinone 2 (0.58 g, 0.0014 mol)
and acrylonitrile (0.08 g, 0.0015 mol) in ethanol
(25 ml) was treated with a few drops of 10%
NaOH solution and the mixture was heated under
reflux for 4 h. The colourless solid which formed
after concentration and cooling was crystallized
from a proper solvent to furnish 6.
A mixture of the pyridazinone 2 (0.75 g, 0.0018
mol) and aromatic aldehydes (0.0019 mol),
namely, benzaldehyde (0.2 g) and/or p-chloro-
benzaldehyde (0.27 g) in ethanol (20 ml) was
treated with 4% ethanolic sodium hydroxide solu-
tion (20 ml) and the whole mixture was refluxed
for 3 h. The solid product which formed after cool-
ing and acidification was filtered off and crystal-
lized from a suitable solvent to furnish 10a,b.
4-Benzylamino-2-hydroxymethyl-6-(5,5-dioxo-
dibenzothiophen-2-yl)-4,5-dihydropyridazin-
3-one (7)
A solution of pyridazinone 2 (1.58 g, 0.0038
mol) in methanol (25 ml) was treated with form-
aldehyde (1.14 g, 0.038 mol), and the reaction mix-
ture was refluxed for 6 h. The colourless solid
which precipitated after cooling, filtered off, dried
and crystallized from a suitable solvent to afford 7.
4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-3-o-(pht- or tos-amino acid)-4,5-dihydro-
pyridazine derivatives (11,12)a,b
An N-phthalyl or N-tosylamino acids, namely,
glycine and DL-alanine (0.001 mol) and pyridazi-
none 2 (0.5 g,0.001 mol) were dissolved in tetrahy-
drofuran (50 ml). The reaction mixture was cooled
to 0 ∞C, then dicyclohexylcarbodiimide (0.021 g)
was added and the mixture stirred for 2 h at 0 ∞C,
left for 24 h at 0 ∞C and for another 24 h at r.t.
The dicyclohexylurea was filtered off, the filterate
9-Benzylamino-7-(5,5-dioxodibenzothiophen-
2-yl)-2,3,4,8,9-pentahydropyridazino[1,6-a]-
1,3,5-triazin-2-one (8)
A mixture of 2-hydroxymethyl pyridazinone 7 evaporated in vacuo and the residue recrystallized
(0.54 g, 0.0012 mol) and urea (0.09 g, 0.0015 mol) from a suitable solvent to furnish (11, 12)a,b
was heated in an oil-bath at 180 ∞C for 3 h, cooled respectively.
,
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A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
675
4-Benzylamino-3-chloro-6-(5,5-dioxodibenzo-
thiophen-2-yl)-4,5-dihydropyridazine (13)
A mixture of 14 (0.52 g, 0.0012 mol) and 2,4-
pentanedione (0.15 g, 0.0015 mol) in ethanol
(25 ml) was heated at reflux for 4 h. The solid that
separated upon cooling was filtered off and crys-
tallized from a suitable solvent to furnish 17.
A mixture of pyridazinone 2 (3.5 g, 0.0084 mol),
POCl3 (41.3 g, 0.27 mol) and PCl5 (2.5 g, 0.012
mol) was refluxed on a steam bath for 4 h. The
reaction mixture was poured gradually on crushed
ice and the solid that separated was filtered off
and crystallized from a suitable solvent to afford
13.
8-Benzylamino-6-(5,5-dioxodibenzothiophen-2-
yl)-1,2,4-triazolo[4,3-b]-7,8-dihydropyridazine (18)
The hydrazinopyridazine 14 (0.52 g, 0.0012 mol)
in AcOH (25 ml) was heated under reflux for 8 h.
The solid separated after concentration and cool-
ing was crystallized from a proper solvent to give
18.
4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-3-hydrazino-4,5-dihydropyridazine (14)
A mixture of compound 13 (2.2 g, 0.005 mol)
and hydrazine hydrate (0.35 g, 0.007 mol) in etha-
nol (50 ml) was heated under reflux for 6 h. The
reaction mixture was concentrated to one third its
orignial volume and allowed to cool. The resulting
solid which deposited was filtered off and crystal-
lized from a suitable solvent to give 14.
Independent synthesis of 18
A mixture of 3-chloropyridazine 13 (0.52 g,
0.0012 mol) and acetylhydrazine (0.09 g, 0.0012
mol) in n-butanol (30 ml) was heated under reflux
for 48 h. The solid product that separated after
concentration and cooling was crystallized from a
proper solvent to yield a product identified to be
18 by mp and mmp determination.
Independent synthesis of 14
(i) 4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-4,5-dihydropyridazin-3(2H)-thione (15)
8-Benzylamino-6-(5,5-dioxodibenzothiophen-2-
yl)-1,2,3,4-tetrazolo[1,5-b]-7,8-dihydropyridazine
(19)
A mixture of pyridazinone 2 (0.8 g, 0.0019 mol)
in (25 ml) of xylene and (2.0 g, 0.009 mol) of P2S5
was heated under reflux for 3 h, filtered while hot
and left to cool. The product separated was crys-
tallized from a suitable solvent to yield the corre-
sponding thione derivative 15.
(ii): The thione derivative 15 (0.5 g, 0.0012 mol)
and hydrazine hydrate (0.1 g, 0.002 mol) in ben-
zene (25 ml) was heated under reflux for 3 h. The
solid obtained after concentration and cooling was
crystallized from a proper solvent to yield a pro-
duct identified to be 14 by mp and mmp determi-
nation.
To a solution of hydrazinopyridazine 14 (0.52 g,
0.0012 mol) dissolved in 10% aq. HCl (10 ml) was
added a solution of sodium nitrite (0.1 g, 0.0014
mol) dissolved in water (2 ml) dropwise under
cooling and the mixture was allowed to stand for
45 min. The mixture was basified with solid
NaHCO3, extracted into CHCl3 and the organic
layer was dried (Na2SO4). Solvent was removed in
vacuo and the residue was crystallized from a
proper solvent to give 19.
Independent synthesis of 19
4-Benzylamino-6-(5,5-dioxodibenzothiophen-
2-yl)-3-[1N-(3-methylpyrazolin-5-one)]-
4,5-dihydropyridazine (16)
A mixture of chloropyridazine 13 (0.52 g, 0.0012
mol) and NaN3 (0.1 g, 0.0015 mol) in DMF (25 ml)
was refluxed for 6 h. The reaction mixture was
evaporated to dryness in vacuo and the residue
was recrystallized from a proper solvent to give a
product identified to be 19 by mp and mmp deter-
mination.
A mixture of 14 (0.52 g, 0.0012 mol) and ethyl
acetoacetate (0.2 g, 0.0015 mol) in ethanol (25 ml)
was refluxed for 6 h. The solid that separated, after
concentration and cooling, was crystallized from a
suitable solvent to give 16.
Acknowledgment
4-Benzylamino-3-(3,5-dimethylpyrazol-1-yl)-
6-(5,5-dioxodibenzothiophen-2-yl)-4,5-dihydro-
pyridazine (17)
The authors are grateful to Dr. M.Amer, Botany
Department, Faculty of Science, Benha University,
for biological evaluation.
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676
A. A. F. Wasfy et al. · α,ꢀ-Unsaturated 4-Oxo Acids in Heterocyclic Synthesis, III
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