Utility of 1-(2,4-dimethoxyphenyl)-3-aryl-prop-2-ene-1-ones as ring transformer in preparing heterocyclic compounds and their potential biological activities

Article abstract of DOI:10.1080/10426500490257041

As an effort to synthesize new heterocyclic compounds, which would be expected to have a pharmacological and biological activities, we report here the reactivity of 1-(2,4-dimethoxyphenyl)-3-aryl-2-propen-1-ones (Ia&b), as Michael acceptors under differen

Full text of DOI:10.1080/10426500490257041

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Phosphorus, Sulfur, and Silicon and the Related
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UTILITY OF 1-(2,4-DIMETHOXYPHENYL)-3-ARYL-PROP-2-
ENE-1-ONES AS RING TRANSFORMER IN PREPARING
HETEROCYCLIC COMPOUNDS AND THEIR POTENTIAL
BIOLOGICAL ACTIVITIES
M. A. I. Salem a , E. A. Soliman a , M. B. Smith b , M. R. Mahmoud a & M. E. Azab a
a Ain Shams University , Abbassia, Cairo, Egypt
b Connecticut State University , Connecticut, USA
Published online: 11 Aug 2010.
To cite this article: M. A. I. Salem , E. A. Soliman , M. B. Smith , M. R. Mahmoud & M. E. Azab (2004) UTILITY OF 1-(2,4-
DIMETHOXYPHENYL)-3-ARYL-PROP-2-ENE-1-ONES AS RING TRANSFORMER IN PREPARING HETEROCYCLIC COMPOUNDS AND
THEIR POTENTIAL BIOLOGICAL ACTIVITIES, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:1, 61-76, DOI:
10.1080/10426500490257041
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Phosphorus, Sulfur, and Silicon, 179:61–76, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490257041
UTILITY OF 1-(2,4-DIMETHOXYPHENYL)-3-ARYL-
PROP-2-ENE-1-ONES AS RING TRANSFORMER IN
PREPARING HETEROCYCLIC COMPOUNDS AND
THEIR POTENTIAL BIOLOGICAL ACTIVITIES
M. A. I. Salem,a E. A. Soliman,a M. B. Smith,b
M. R. Mahmoud,a and M. E. Azaba
Ain Shams University, Abbassia, Cairo, Egypt;a and
Connecticut State University, Connecticut, USAb
(Received May 20, 2003; accepted July 17, 2003)
As an effort to synthesize new heterocyclic compounds, which would be
expected to have a pharmacological and biological activities, we report
here the reactivity of 1-(2,4-dimethoxyphenyl)-3-aryl-2-propen-1-ones
(Ia&b), as Michael acceptors under different conditions, towards differ-
ent Michael donors namely, pyrazolin-5-one, 2-cyanomethylthiazolidin-
4-one, thiobarbituric acid, cyclohexanone, and ethyl cyanoacetate af-
fording the adducts bispyrazolo[5,4-b]-4H-pyranes III, 5-oxopyrazolin-
4-yl-propan-1-ones IV, 2-(4-oxothiazolidine-2-yl)-5-oxopentano-carbo-
nitrile XI, 4-oxo-4H-pyranol[2,3-d]tetrahydropyrimidin-2-thiones XVI,
cyclohexano[b]-4H-pyran XVII, ethyl-5-oxo-pentanoate XVIII, and 1-
aroyl-2-arylcyclopropanes XIX respectively. Fusion of XI with excess
ammonium acetate yielded 2-aminopyridine derivative XII and 2-
aminotetrahydropyridine derivative XIII. Diazotization of XII by treat-
ment with HNO2 at 0◦C produced the diazonium chloride derivative
XIV which underwent coupling reaction with phenolic compounds to
yield the azo-disperse dyes XV. Alkaline hydrolysis of XVIII afforded
the corresponding acid XX which reacted with hydrazines by fusion to
yield the diazapinone derivatives XXI. The structures of the products
obtained were confirmed by elemental analysis, infrared, 1H-NMR, 13C-
NMR, and mass spectra. The biological activity for some synthesized
products are screened.
Keywords: 2-Cyanomethylthiazolidin-4-one; 4-oxo-4H-pyrano[2,3-
d]tetrahydropyrimidin-2-thiones; azo-disperse dyes; diazapinone
pyrazolin-5-one; thiobarbituric acid
The authors would like to express their appreciation to Prof. Dr. K. P. Zeller, Institute
fur Organische Chemie, Tubingen University, Tubingen, Germany for performing some
1H- and 13C-NMR, and mass spectra. Many thanks to Prof. Dr. Zahraa Karam El-Din,
Microbiology Department, Faculty of Science, Ain Shams University for achievement of
biological activities evaluation of some newly synthesized compounds.
Address correspondence to M. A. I. Salem, Synthetic Organic Laboratory, Chemistry
Department, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt.
61

62
M. A. I. Salem et al.
Pyrazolin-5-one derivatives were found to exhibit antiinflammatory,1,2
herbicidal,3–6 fungicidal,7–9 bactericidal,7,10 and antiarthitic1 effects,
and they have been used as plant growth regulators.6 Therefore, we
attempted to prepare pyranopyrazole derivatives according to the pub-
lished articles.11,12 The reaction of chalcone I with pyrazolone deriva-
tives IIa (R Ph) and IIb (R Me), has been previously claimed to afford
the normal Michael adduct13a or the pyranopyrazole derivative. Herein,
no pyranopyrazole could be isolated in the above reaction. Instead,
we have found that the reaction products were the bis-pyrazolopyrane
III as colorless crystals together with the Michael adduct IV and 2,4-
dimethoxy acetophenone. Compounds III were allowed to react with
aqueous potassium hydroxide (10%) to yield (Va–d) respectively. The
structures of Va–d were found to be identical with those previously
prepared.13b
Compound III has further support by identity (m.p., mixed m.p.,
TLC, and IR comparison) with an authentic sample resulted either from
the reaction of 4-arylidene-1-phenyl-3-methylpyrazolin-5-one with II
(1:1 molar ratio) or prepared from the reaction of II with suitable aro-
matic aldehyde (2:1 molar ratio).
In order to obtain further information on the enolic structure of V,
the complexation reaction of Va&b with Cu+2 was investigated.14 To
ethanolic solution of Va&b, copper acetate [Cu(OAc)2] solution was
added which rapidly formed cupric salts VIa&b. According to the ele-
mental analysis of VIa&b, the ratio of Cu and V was 1:1. IR spectra of
VI did not show the two characteristic bands to be strongly H-bonded
enolic-OH at 2600–2500 cm−1 due to cooperative proton transfer15
and around 1400 cm−1 as the bending vibrations of enolic C-OH
groups,16a−c indicating the absence of the enolic OH group (Scheme 1).
The adducts IVb&c were fused with thiourea in an oil-bath at 160◦C
and/or hydrazine hydrate (80%) in an oil-bath at 140◦C to give VIIa&b
and VIIIa&b, respectively.
Refluxing IVb&c with hydroxylamine hydrochloride in pyridine
and/or with acetic anhydride (freshly distilled) for 8 h afforded the oxime
IXa&b and the acetate Xa&b respectively (Scheme 1).
On the other hand, the Michael adduct (XI) was formed upon treat-
ment of chalcone Ia with 2-cyanomethyl-thiazolidin-4-one. Treatment
of XI with fused ammonium acetate in an oil bath at 160–170◦C af-
forded (XII) and (XIII).17,18 Diazotization of XII with NaNO2/HCl pro-
duced the diazonium chloride salt XIV which, on coupling with phenolic
compounds, afforded the azo-disperse dyes XV.
The reaction of chalcone with thiobarbituric has been previously
reported to afford pyranopyrimidine derivatives.19 Herein, the re-
action of chalcones Ia&b with thiobarbituric in boiling acetic acid

Pyrazolinones
63
SCHEME 1
or by fusion at 130–140◦C, using anhydrous zinc chloride, pro-
duced solid products which were identified to be 4-oxo-4H-pyrano[2,3-
d]tetrahydropyrimidin-2-thione derivatives (XVIa&b).
Sammour et al.20 reported that chalcones reacted with cyclohexanone
in ethanolic sodium hydroxide solution to give the normal Michael
adducts. Herein the reaction of the chalcones (Ia&b) with cyclohex-
anone afforded the Michael cyclized product21 (XVIIa&b).
It has been reported that the reaction of ethyl cyanoacetate with dif-
ferent α,β-unsaturated ketones gave different Michael adducts accord-
ing to reaction conditions.22,23 In the present work, we reinvestigated

64
M. A. I. Salem et al.
SCHEME 2
the base-catalyzed addition of ethyl cyanoacetate to the title compound
Ia&b which gave the Michael adduct (XVIIIa&b) and the cyclopropane
(XIXa&b).
Acid hydrolysis of XVIIIa&b using conc.H2SO4 afforded acids
(XXa&b). Fusion of (XXa&b) with hydrazine hydrate furnished the
diazapinone derivatives (XXIa&b) (Scheme 2).
EXPERIMENTAL
Melting points reported are uncorrected. IR spectra were recorded
on mattson 1000 F.T.I.R. spectrometer and 283 Perkin-Elmer spec-
trophotometer using KBr as a wafer technique. The 1H-NMR spec-
tra and 13C-NMR were determined on Bruker AC 270 and Bruker AC
250(200 MHz). In all 1H-NMR and 13C-NMR experiments, the internal
standard was TMS (in δ-scale). All chemical shifts were downfield from
TMS.
The G.C. mass spectra were determined on AEI MS-902 mass spec-
trometer. Mass spectra were determined on MS-TSQ 70 Finnigan MAT.

Pyrazolinones
65
Reaction of Ia&b with 1-Phenyl-3-substitutedpyrazolin-
5-one (IIa,b); Formation of 4-Aryl-bis-1-phenyl-3-
substitutedpyrazolo[5,4-b]-4H-pyran (IIIa–d) and
3-Aryl-1-(2,4-dimethoxyphenyl)-3-(1-phenyl-3-
substituted-5-oxopyrazolin-4-yl)-propan-1-one (IVa–d)
A mixture of chalcones20,24 Ia or Ib (0.01 mmol in 20 mL ethanol) and
pyrazolones IIa or IIb (0.012 mmol, in 20 mL ethanol) was refluxed, in
the presence of 2 mL piperidine, for 6 h. A white solid, which was formed
on hot, was filtered off and recrystallized from acetic acid giving IIIa–d
respectively. Slow evaporation of the filtrate produced another white
crystals, which was recrystallized from ethanol yielding the adducts
IVa–d respectively (c.f. Table I).
Compounds IIIa–d were prepared authentically by two methods.
Method A: via a one step reaction by reacting IIa or IIb with p-
anisaldehyde or p-tolualdehyde (2:1 molar ratio) in the presence of a
few drops of piperidine. After stirring for 5 min at room temperature,
the precipitates are obtained. Method B: via a two step reaction, by
fusion of IIa or IIb with p-anisaldehyde or p-tolualdehyde (1:1 molar
ratio) at 120–130◦C for 2 h to give the 4-arylidene derivatives which on
treatment with another mole of IIa&b in ethanol, in the presence of a
few drops of piperidine, and refluxing for 4 h gave IIIa–d.
1H NMR spectrum of IIIa (DMSO-d6) δ at 8.2 (d,d, 4H, p-substituted
phenyl ring protons), at 7.5–6.9 (m, 10H, two phenyl ring protons), at
5.8 (s, 1H, C4-H pyran), at 3.3 (s, 3H, p-methoxy protons) and at 2.2 (s,
1
6H, the two methyl protons); H NMR of IIIc (DMSO-d6) shows δ at
7.9–7.7 (d, d, 4H, aromatic protons of the p-substituted phenyl ring), at
7.3-6.9 (m, 10H, aromatic protons of the phenyl groups), at 5.6 (s, 1H,
C4-H pyran), at 2.3 (s, 6H, two methyl protons of the pyrazole rings) and
at 2.1 (s, 3H, methyl protons of the tolyl ring); MS, m/e (%) 432 [M+·]
(2.3%), 276 (100%), 248 (20.1%), 185 (44.5%), 174 (7.8%), 156 (7.4%),
144 (12.1%), 134 (24.4%), 132 (17.4%), 118 (18.0%), 106 (4.1%), 105
1
(10.3%), 92 (5.6%), 91 (2.5%), 77 (17.7%), 65 (7.1%); H NMR of IIId
(DMSO-d6) shows signals at 8.2–8.0 (d,d 4H, aromatic protons of the
p-substituted phenyl ring), at 7.4–7.0 (m, 20H, aromatic protons four
phenyl groups), at 5.85 (s, 1H, C4-H pyran) and at 2.2 (s, 3H, methyl
protons); MS m/e (%) 556 [M+·] (3.3%), 396 (100%), 368 (22.6%), 285
(42.3%), 218 (6.1%), 194 (14.9%), 182 (11.2%), 134 (26.0%), 121 (12.2%),
117 (19.2%), 106 (4.4%), 91 (6.1%), 77 (18.5%) and 65(8.8%). IR data are
shown in Table II.
1H NMR of IVb (DMSO-d6) δ at 8.1 (d, 2H, J = 9.1 Hz, o-H’s in p-
methoxy-phenyl ring), 7.5–6.8 (m, 15H, aromatic protons), 4.1 (d, 1H, J
= 8.6 Hz, C4-H pyrazolone), 3.25 (s, 3H, OMe), 3.4 (s, 6H, 2 OMe), at 2.9
(m, 1H, benzylic proton) and at 2.5 (d, 2H, J = 11.0 Hz, -CH2CO). MS,

66
M. A. I. Salem et al.
TABLE I Physical Data of Newly Synthesized Products
Analysis Calcd. Found
Solvent
Compd. m.p. ◦C/(color)
yield (%)
M.F./(m. wt)
C%
H%
N%
Cu%
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
Va
212–214
(white)
217–219
(white)
214–216
(white)
221–223
(white)
124–126
(white)
102–104
(white)
127–129
(white)
113–115
(white)
171–173
(Orange)
176–178
(Orange)
164–166
(Light red)
172–174
(Light red)
>360
AcOH
(46)
AcOH
(43)
AcOH
(43)
AcOH
(41)
C28H24N4O2 74.98 5.39
(448) 74.82 5.17
C38H28N4O2 79.70 4.93
12.49
12.30
9.78
(572)
C28H24N4O
(432)
C38H28N4O
(556)
79.53 4.75
77.75 5.59
77.62 5.50
81.99 5.07
81.90 4.92
9.59
12.95
12.80
10.06
9.88
5.93
5.79
5.24
5.05
6.14
5.95
5.41
5.23
12.01
11.85
9.49
L.P. 80–100◦C C28H28N2O5 71.19 5.93
(40)
L.P. 80-100◦C C33H30N2O5 74.16 5.62
(38) (534) 73.98 5.44
L.P. 80-100◦C C28H28N2O4 73.68 6.14
(38) (456) 73.49 6.03
L.P. 80-100◦C C33H30N2O4 76.45 5.79
(472)
71.02 5.81
(37)
EtOH
(85)
EtOH
(82)
EtOH
(78)
EtOH
(74)
—
(88)
—
(91)
EtOH
(41)
EtOH
(40)
EtOH
(41)
EtOH
(41)
Benzene
(53)
Benzene
(49)
L.P-B
(65)
L.P-B
(61)
(518)
28H26N4O3 72.09 5.62
(466) 71.93 5.43
38H30N4O3 77.27 5.12
(590) 77.11 4.91
28H26N4O2 74.65 5.82
(450) 74.49 5.70
C38H30N4O2 79.42 5.26
(574) 79.25 5.11
28H24N4O3Cu 63.69 4.58
(527.5) 63.49 4.41
28H24N4O2Cu 65.68 4.72
(512) 65.51 4.61
34H32N4O4S 68.90 5.44
(592) 68.79 5.40
29H30N4O3S 67.68 5.88
(514) 67.74 5.70
C33H32N4O4 72.24 5.88
(548) 72.46 6.09
28H30N4O3 71.47 6.43
(470) 71.57 6.44
C33H31N3O5 72.11 5.69
(549) 71.91 5.46
28H29N3O4 71.32 6.20
(471) 71.40 6.15
C35H32N2O6 72.90 5.59
(576) 72.77 5.48
C30H30N2O5 72.27 6.06
(498) 72.06 5.90
76.28 5.61
C
C
C
Vb
9.30
Vc
12.44
12.27
9.75
Vd
9.58
VIa
VIb
VIIa
VIIb
VIIIa
VIIIb
IXa
IXb
Xa
C
C
10.61 12.03
10.44 12.21
10.94 12.41
10.84 12.51
9.45
9.51
10.89
10.98
10.21
10.27
11.91
12.01
7.65
7.87
8.91
8.76
4.86
(Brown)
>360
(Brown)
196–198
(Yellow)
191–193
(Yellow)
167–169
(Orange)
163–165
(Orange)
181–183
(Pale Yellow)
180–182
(Pale Yellow)
55–57
C
C
C
C
(Orange)
52–54
(Orange)
4.68
5.62
5.41
Xb
(Continued on next page)

Pyrazolinones
67
TABLE I Physical Data of Newly Synthesized Products (Continued)
Analysis Calcd. Found
Solvent
Compd.
m.p. ◦C/(color)
yield (%)
M.F./(m.wt)
C%
H%
N%
Cu%
XI
285-288
(Deep brown)
180-183
(Riddish brown)
147-150
(Yellow)
224-226
(Reddish brown)
191-193
(Reddish brown)
316-318
aq.EtOH C23H22N2O5S 63.00 5.06
6.39
6.28
9.65
9.47
9.56
9.38
9.49
9.67
11.84
12.00
6.60
6.41
6.86
6.79
—
—
—
—
—
—
—
—
—
(59)
AcOH
(49)
EtOH
(41)
EtOH
(74)
EtOH
(78)
AcOH
(89)
AcOH
(87)
(438)
C23H21N3O4S 63.43 4.86
(435) 63.26 4.77
C23H25N3O4S 62.85 5.73
(439) 62.69 5.51
C33H26N4O5S 67.10 4.44
(590) 66.93 4.56
32H25N5O5S 64.97 4.23
(591) 65.08 4.12
22H20N2O5S 62.26 4.75
(424) 62.09 4.60
22H20N2O4S 64.69 4.94
63.14 5.14
XII
XIII
XVa
XVb
C
C
C
XVIa
XVIb
XVIIa
XVIIb
XIXa
XIXb
XXa
(Red)
313-315
(Reddish-brown)
111-113
(408)
24H26O4
(378)
64.53 4.78
76.17 6.92
75.95 6.74
79.53 7.23
79.39 7.17
73.06 6.45
72.96 6.35
77.00 6.80
76.91 6.69
67.03 6.19
67.12 6.01
70.16 6.48
69.98 6.67
EtOH
(41)
C
(white)
105-107
(white)
133-135
(white)
127-129
(white)
271-273
EtOH
(40)
C24H26O3
(362)
Ethanol
(9)
Ethanol
(8)
Benzene
(67)
C
C
C
19H20O4
(312)
19H20O3
(296)
20H22O6
(358)
(Buff)
282-284
(Buff)
—
—
—
XXb
Benzene
(63)
C20H22O5
(342)
XXIa
XXIb
148-150
(white)
140-142
(white)
EtOH
(42)
EtOH
(38)
C
20H22N2O4 67.78 6.26
(354) 67.67 6.09
20H22N2O3 70.99 6.55
(338) 70.84 6.40
7.90
7.72
8.28
8.20
C
m/e (%) 534 [M+·] (4.5%), 354 (11.1%), 298 (88.0%), 283 (39.1%), 236
(100%), 165 (17.1%), 132 (2.7%), 131 (19.6%), 103 (2.4%), 101 (2.0%), 91
(13.6%), 77 (2.7%), 65 (2.0%); 13C NMR is shown in Figure 1.
1H NMR of IVc (DMSO-d6) δ at 8.2–6.7 (m, 12H, arom. H’s,) 4.2
(d, 1H, J = 8.7 Hz, C4-H pyrazolone), 3.9 (s, 6H, 2 OMe), 3.1 (m, 1H,
benzylic proton), 2.7 (d, 2H, J = 11.0 Hz, CH2CO) and at 2.4 (s, 6H, two
methyl protons).
1H NMR of IVd (DMSO-d6) δ at 8.1–7.1 (m, 17H, arom. H’s), 4.1 (d,
1H, J = 9.2 Hz, C4-H pyrazolone), 3.9–3.8 (two s, 6H, 2 OMe), 3.2 (m,
1H, benzylic proton), 2.8 (d, 2H, J = 11.1 Hz, CH2CO) and at 2.3 (br,
s, 3H, Me-Ar); MS, m/e (%) 282[M-236](17.1%), 236(69.4%), 165(100%),
150(14.6%), 131(2.2%), 122(12.2%), 116(1.1%), 103(26.3%), 91(24.5%),
77(17.8%).

68
M. A. I. Salem et al.
TABLE II IR Data of the Newly Synthesized Products
νC
O
νC
(pyrazolone)
O
Compd. νC
νC
(ketone)
/νC
νCH(aliph.)
νCH(arom.)
νNH/νOH
C
N
N
IIIa
IIIb
IIIc
IIId
IVa
IVb
IVc
IVd
Va
1605 1620
1600 1615
1595 1620
1605 1615
1605 1620
1610 1620
1605 1615
1600 1610
1595 1615
1605 1620
1610 1620
1605 1615
1595 1605
1570 1610
1605 1630
1595 1620
—
—
—
—
—
—
—
1715
1720
1720
1725
1715
1720
1720
1725
—
2980, 2880, 2720 3060
2960, 2870, 2725 3040
2950, 2860, 2710 3035
2970, 2865, 2710 3050
—
—
—
—
3440
3450
3460
3460
3450
3445
3460
3455
—
—
1660
1670
1660
1660
—
—
—
—
—
—
—
—
—
—
—
—
2945, 2860
2980, 2870
2930, 2850
2945, 2860
2940, 2850
2970, 2880
2965, 2875
2975, 2880
2960, 2835
2970, 2845
2930, 2865
2920, 2855
2960, 2850
2935, 2860
2950, 2860
2930, 2850
2980, 2855
3080
3070
3065
3080
3055
3065
3060
3070
3080
3065
3085
3060
3065
3010
3030
3020
3060
Vb
Vc
Vd
VIa
VIb
VIIa
VIIb
VIIIa 1605 1615
VIIIb 1600 1610
IXa
IXb
Xa
—
—
1720
1710
1710
1725
1720
1715
—
3455
3430
3450
3380
3450
3430
—
1605 1620
1600 1615
1600 1615 1655 aroyl,
1700 acetyl
Xb
1600 1610 1655 aroyl,
1700 acetyl
1600 1610 1640,1665
—
2965, 2845
3070
3040
—
XI
XII
XIII
XVa
XVb
2245
—
—
2990, 2850
2970, 2850
2980, 2860
2970,2855
2975, 2865
2930, 2860
—
1595 1615
1600 1615
1590 1615
1590 1615
1670
1670
1665
3030 3460-3480 (br.)
3040 3460-3470 (br.)
3030
3035
—
3450
3455
1660
XVIa 1605 1610
XVIb 1600 1615
XVIIa 1610
1665,
1185 νC
1655,
1180 νC
—
—
—
—
—
3075 3450-3480 (br.)
S
S
2925, 2855
3070 3445-3480 (br.)
2960, 2910
2860
2965, 2910
2850
3080
3070
—
—
XVIIb 1610
—
XVIIIa 1600
XVIIIb 1605
XIXa 1600
1735, 1670
1730, 1660
1660
2240
2230
—
2980, 2840
2960, 2835
2975, 2935
2900, 2840
2970, 2930
2900, 2850
2945, 2850
3035
3015
3020
3500
3450
—
XIXb 1600 1620
1650
—
—
3015
3045
—
XXa
1605
—
1670 aroyl,
1710 acid
3550 (br.)
(Continued on next page)

Pyrazolinones
69
TABLE II IR Data of the Newly Synthesized Products (Continued)
νC
O
νC
(pyrazolone)
O
Compd. νC
νC
(ketone)
/νC
νCH(aliph.) νCH(arom.)
νNH/νOH
C
N
N
XXb
1610
—
1665 aroyl,
1705 acid
1660
—
—
—
2935, 2840
3045
3040
3030
3500 (br.)
XXIa
XXIb
1600 1620
1605 1625
2990, 2940
2890,2825
2980, 2940
2880,2825
3445-3480 (br.)
3440-3490 (br.)
1660
Reaction of III with Aqueous Potassium Hydroxide
(10%); Formation of bis-(1-Phenyl-3-substituted-
5-oxopyrazolin-4-yl) Aryl Methanes (Va-d)
To (0.01 mmol) of IIIa–d, 40 mL aqueous alcoholic solution of potas-
sium hydroxide (10%) was added, the reaction mixture was refluxed for
6 h followed by concentrating the solution then pouring over ice/HCl
mixture, an orange solid was precipitated, which was filtered off, dried,
and recrystallized from ethanol giving the adducts Va–d respectively.
Some of the adducts IIIa–d were previously prepared by other
methodology.13b
Reaction of Va&c with Cupric Acetate; Formation
of Copper Salt VIa&b
A solution of cupric acetate monohydrate (0.05 mmol) in ethanol (15 mL)
was added dropwise into ethanolic solution (15 ml) containing Va or Vc
(0.01 mmol) with stirring. A brown precipitate was formed immedi-
ately. After additional stirring for 0.5 h, the precipitate was separated
by centrifugation, washed with ethanol (95%) and water several times
then again with (95%) ethanol and then dried affording the copper salts
VIa&b.
Reaction of IVb&c with Thiourea and/or Hydrazine
Hydrate; Formation of N-thiocarbamido-3-aryl-1-(2,4-
dimethoxyphenyl)-3-(1-phenyl-3-substituted-5-oxo-
pyrazolin-4-yl)propan-1-one Imine (VIIa,b) and 3-Aryl-1-
(2,4-dimethoxyphenyl)-3-(1-phenyl-3-substituted-5-
oxopyrazolin-4-yl)propan-1-one hydrazones (VIIIa,b)
A mixture of IVb or IVc (0.01 mmol) was heated with thiourea
(0.015 mmol, 1.05 g) and/or hydrazine hydrate (80%) (0.015 mmol,
0.75 g) at 140◦C for 6 h. The reaction mixture was triturated with

70
M. A. I. Salem et al.
FIGURE 1
water and dilute HCl. The crude product was spread over silica gel us-
ing ethylacetate-light petrol 60–80◦C (2:8) as an eluent to separate the
desired adduct using TLC preparative technique, dissolving the spots
in ethylacetate followed by slow evaporation gave an oil product which
on trituration with drops of methanol gave the solid products VIIa&b
and VIIIa&b respectively.
Reaction of IVb&c with Hydroxylamine Hydrocloride;
Formation of 3-Aryl-1-(2,4-dimethoxyphenyl)-3-(1-
phenyl-3-substituted-5-oxopyrozolin-4-yl)propan-1-one
oximes (IXa&b)
A mixture IVb or IVc (0.01 mmol) and hydroxylamine hydrochloride
(0.015 mmol, 1.05 g) was refluxed in pyridine (15 mL) for 6 h. The

Pyrazolinones
71
reaction mixture was poured over ice and HCl, a pale yellow solid was
separated out, filtered off, washed with H2O several times, dried, and re-
crystallized from the proper solvent affording the corresponding oximes
IXa&b respectively.
1H NMR of IXa (CDCl3) exhibited the following signals at δ 11.4 (s,
1H, N OH), 8.3 (d, 2H, J = 9.1 Hz, o-H’s in p-methoxyphenyl ring), 7.8-
6.8 (m, 15H, aromatic protons), 4.2 (d, 1H, J = 8.6 Hz, C4-H pyrazolone),
3.3 (s, 3H, OMe), 3.5 (s, 6H, 2 OMe), at 2.9 (m, 1H, benzylic proton) and
at 2.5 (d, 2H, J = 11.0 Hz, CH2CO).
Reaction of IVb&c with Acetic Anhydride; Formation of
3-(5-Acetoxy-1-phenyl-3-substituted-5-oxopyrazolin-4-
yl)-3-aryl-1-(2,4-dimethoxyphenyl)propan-1-ones (Xa&b)
A solution of the products IVb or IVc (0.01 mmol) in acetic anhydride
(20 ml) was refluxed for 8 h. The reaction mixture was concentrated
to its half volume then poured over ice/water, an orange solid was de-
posited out which was recrystallized from the proper solvent yielding
the products Xa&b respectively.
1H NMR spectrum of Xa (CDCl3) exhibits the following signals at δ
(ppm):- 7.7-6.4 (m, 17H, arom. H’s), 4.4 (t, 1H, CHArꢁ), 3.9 (s, 3H, OMe)
3.8-3.7 (two s, 6H, 2 OMe), 2.8 (d, 2H, J = 11.4 Hz, CH2CO), and 2.0 (s,
3H, Me-CO); MS m/e (%) 354[M-222](21.2%), 298(88.0%), 279(6.8%),
247(5.5%), 236(100%), 180(3.9%), 165(17.6%), 150(3.1%), 135(17.6%),
132(2.1%), 131(10.0%), 121(38.5%), 102(8.2%), 91(4.2%), and 77(2.1%);
13C NMR is shown in Fig. 1.
Reaction of Chalcone Ia with 2-Cyanomethylthiazolidin-
4-one; Formation of 5-(2,4-Dimethoxyphenyl)-
3-(4-methoxyphenyl)-2-(4-oxothiazolidin-2-yl)-
5-oxopentano-carbonitrile (XI)
2-Cyanomethyl thiazolidin-4-one (0.01 mmol, 1.4 g) in 20 mL ethanol
and sodium ethoxide (1 g sodium in 30 mL absolute ethanol) was added
dropwise to an alcoholic solution of chalcone Ia (0.01 mmol 2.98 g) in
20 mL ethanol with stirring at room temperature for 30 min, then the
reaction mixture was refluxed for 12 h, left to cool then neutralized by
ice/HCl. The solid that precipitated out was filtered off, washed with
water several times, then recrystallized from aq. ethanol to produce
the adduct XI.
1H NMR spectrum of XI (acetone-d6) shows from low to high field sig-
nals at δ 8.5-7.9 (m, 7H, aromatic), 4.3 (d, 1H, J = 9.3 Hz, -CH-CN), 3.7 (s,
2H, S-CH2CO-), 3.4 (s, 9H, 3 OMe), 3.0-2.8-(m, 1H, benzylic proton) and
at 2.7 (d, 2H, J = 10.6 Hz, Ar-CO-CH2-); MS m/e (%) 438[M+·] (1.0%),

72
M. A. I. Salem et al.
298(58.3%), 283(36.7%), 272(2.1%), 270(30.9%), 255(9.9%). 165(77.7%),
141(3.1%), 135(25.8%) 121(100%) 107(10.6%), and 92(10.2%); 13C NMR
is shown in Figure 1.
Reaction of XI with Ammonium Acetate; Formation of
2-Amino-6-(2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-
3-(4-oxothiazolidin-2-yl)pyridine (XII) and 2-Amino-6-
(2,4-dimethoxyphenyl)-4-(4-methoxypenyl)-3-(4-
oxothiazolidin-2-yl)tetrahydropyridine (XIII)
On an oil bath, the product X (0.0025 mmol 1.1 g) and 2 g of ammonium
acetate were fused at 170◦C for 4 h. The reaction mixture was poured
over cold water then the solid formed was filtered off and washed with
water several times. Fractional crystallization of the solid product af-
forded compounds XII and XIII respectively.
1H NMR spectrum of XII (CDCl3) exhibits the following signals at δ
(ppm):- 8.4-7.6 (m, 8H, arom. H’s), 4.7 (s, 2H, CH2 of azathiazole ring),
3.7 (s, 9H, 3 OMe), and 3.3 (s, 2H, NH2).
Diazotisation and Coupling of (XII) with Phenolic
Compounds; Formation of Azodisperse Dyes (XV)
A solution of the diazonium chloride (XIV), prepared by diazotizing
10 mmol of XII in hydrochloric acid (6 mL, 6 M) with sodium nitrite
(0.7 g, 10 mmol) in 10 mL water, was stirred for 30 min with cooling in
ice bath to 0–5◦C.
To the solution of phenolic compounds, namely, α-naphthol and/or
8-hydroxy-quinoline (1.44 g, 10 mmol) in ethanol 3 ml and 10 mmol
of NaOH (6 mL, 6 M) was added dropwise while cooling at 0◦C to an
aqueous cold solution of the diazonium chloride XIV in an ice bath with
continuous stirring for additional 15 min, followed by acidification with
aq. HCl (50 mL, 1 M) then the solid formed was filtered off and washed
with water, dried and recrystallized from the proper solvent, to give the
reddish brown azo-disperse dyes (XVa&b) respectively.
1H NMR spectrum of XVa (CDCl3) exhibits the following signals at
δ (ppm):- 10.4 (s, lH, OH), 8.3-7.6 (m, 14H, arom. H’s), 4.8 (s, 2H, CH2
of azathiazole ring), and 3.7 (s, 9H, 3 OMe).
Reaction of Chalcones Ia&b with Thiobarbituric Acid;
Formation of 5-Aryl-7-(2,4-dimethoxyphenyl)-4-oxo-4H-
pyrano[2,3-d]tetrahydropyrimidin-2-thione (XVIa&b)
Method A: A mixture of chalcones Ia or Ib (0.01 mmol) and thiobarbi-
turic acid (0.12 mmol 1.72 g) was refluxed in 30 mL glacial acetic for 6 h.

Pyrazolinones
73
A precipitate was obtained during the reflux which was filtered off and
recrystallized from the proper solvent producing the products XVIa&b
respectively.
Method B: The same reaction was repeated by fusion at 140–150◦C
in the presence of anhydrous ZnCl2 (2 g) for 1 h. The same products
XVIa&b were obtained after pouring over hot water and washing by
water several times.
1H NMR spectrum of XVIa (acetone-d6) showed the characteristic
signals for two NH of thiobarbituric moiety at δ 12.3 and 12.4, at
8.4-7.0 (m, 7H, aromatic and olefinic protons), at 6.3 (d, 1H, J =
14.0 Hz, olefinic proton), at 5.1 (d, lH, J = 10.8 Hz, C4-H pyran)
and at 3.9 and 3.4 (s, 9H, three methoxy protons); MS m/e (%) 262
[M-162+·](100%), 247(58.3%), 283(12.0%), 231(30.0%), 202(22.0%),
188(2.5%),
164(46.5%),
162(16.7%),
160(33.0%),
145(18.0%),
117(27.0%), 89(28.0%) and 63(6.0%).
Reaction of Chalcones Ia&b with Cyclohexanone;
Formation of 4-Aryl-2-(2,4-dimethoxyphenyl)-
cyclohexano[b]-4H-pyran (XVIIa&b)
Cyclohexanone (0.012 mmol, 1.2 mL) was added dropwise to sodium
ethoxide (1 g 30 mL ethanol), then chalcones Ia or Ib (0.01 mmol), in
30 mL ethanol, was added dropwise with stirring at room temperature
for 30 min, then the stirred mixture was warmed on water bath at 40–
60◦C for 12 h, the reaction mixture was concentrated and neutralized
by ice/HCl, the solid obtained was filtered off, dried, then recrystallized
from the proper solvent affording the products XVIIa&b respectively.
1H NMR spectrum of XVIIa (CDCl3) displayed signals at δ 8.1-7.2
(m, 7H, aromatic H), 6.3 (d, 1H, J = 14.0 Hz, olefinic H), 4.9 (d, 1H,
J = 11.2 Hz, C4-H pyran), 3.8 (s, 9H, 3 OMe) and 2.65-1.1 (m, 8H, cy-
clohexyl protons), MS m/e (%) 378[M+·](8.6%), 299(37.1%), 165(100%),
135(3.0%), 134(2.0%), 121(17.0%), 107(7.1%), 80(2.1%), 77(9.0%) and
65(5.1%); 13C NMR is shown in Figure 1.
Reaction of Chalcones Ia&b with Ethyl Cyanoacetate;
Formation of Ethyl 3-Aryl-2-cyano-5-(2,4-dimethoxy-
phenyl)-5-oxopentanoate (XVIIIa&b) and 2-Aryl-1-
(2,4-dimethoxybenzoyl)cyclopropane (XIXa&b)
Ethyl cyanoacetate (0.012 mmol, 1.3 mL) was added to a stirred so-
lution of sodium ethoxide (1 g of Na in 20 mL of absolute ethanol),
then a solution of chalcones Ia or Ib (0.01 mmol, in 20 mL absolute

74
M. A. I. Salem et al.
ethanol) was added dropwise within 1 min. The reaction mixture was
stirred and heated under reflux on water bath for 4 h. The solution was
concentrated, then poured over ice/dil. HCl mixture affording a brown
oil. Extraction with ether and drying over anhydrous MgSO4, produced
a pale brown oil. Trituration of the oil with methanol gave XVIIIa&b
as pale yellow oil (Rf 0.63) in 40–45% yield and XIXa&b as white solid
respectively.
1H NMR spectrum of XIXa (CDCl3, δ ppm) displayed the following
signals:- at 7.7–6.4 (m, 7H, aromatic protons), at 3,9–3.7 (s, 9H, 3 OMe)
and Ar-CO-CH, CH-Ar’ at 3.27 , CH2 at 1.8 due to vicinal and geminal
coupling; MS of XIXa m/e (%) 312[M+·] (2.1%), 298(72.8%), 283(2.5%),
251(2.9%), 180(8.8%), 165 (100%), 137(2.2%), 135(72.9%), 121(4.2%),
107(2.4%) and 77(9.0%); 13C NMR is shown in Figure 1.
Hydrolysis of XVIIIa&b; Formation of 3-Aryl-5-
(2,4-dimethoxyphenyl)-5-oxo-pentanoic Acid (XXa&b)
2 g of XVIIIa or XVIIIb was dissolved in 40 mL conc. H2SO4 (60%) was
stirred at room temperature for 1 h. The reaction mixture was heated
on steam bath for 6 h. with continuous stirring and allowed to cool to
room temperature then poured into ice/water and kept overnight. The
solid product that separated out was filtered off and crystallized from
the proper solvent to give the acids (XXa&b).
1H NMR spectrum of XXa (CDCl3) exhibits the following signals at
δ (ppm):- 2.9 (d, 2H, COCH2, J = 11.2), 3.8 (s, 9H, 3 OMe), 4.2 (d, 2H,
CH2COOH, J = 9.4), 5.9 (m, 1H, benzylic H), 8.6–7.4 (m, 7H, aromatic
H’s) and 11.1 (s, 1H, COOH).
Reaction of the Acids (XXa&b) with Hydrazine Hydrate;
Formation of Diazipenones (XXIa&b)
A solution of (XXa or XXb) (0.01 mmol in 40 ml n-butanol) was stirred
at room temperature for 15 min until all the solid was dissolved then
0.015 mmol (0.7 ml) of hydrazine hydrate (80%) was added dropwise
to the above solution with continuous for another 15 min. The reac-
tion mixture was heated for 4 h concentrated by filtration and crys-
tallized from suitable solvent to give diazipenone derivatives XXIa&b
respectively.
1H NMR spectrum of XXIa (CDCl3) exhibits the following singnals
at δ (ppm):- 3.1 (d, 2H, C4, J = 7.8), 3.7 (s, 9H, 3 OMe), 4.3 (d, 2H, C6, J
= 11.3), 5.8 (m, 1H, C5), 7.1–8.3 (m, 7H, aromatic protons), and 9.2 (s,
1H, NH).

Pyrazolinones
75
TABLE III Biological Activity of Some Compounds
Inhibition
Aspergillus
Candida
E. coli
St. aur
A∗
MIC
Compd.
A∗
MIC
A∗
MIC
A∗
MIC
IIIa
IIIc
IVa
IVc
Va
Vb
VIIa
VIIIa
IXa
XIIa
XIIb
XVIa
XVIb
VVIIIa
XXa
XXIa
—
—
—
—
—
—
—
64
64
32
—
64
64
64
32
32
—
64
—
—
—
—
—
+
—
—
—
+
—
+
128
—
128
128
32
128
64
—
128
64
128
32
32
—
+
—
128
—
128
128
32
128
64
—
128
64
128
32
64
—
+
—
—
+
+
++
++
+ + +
—
++
++
++
+ + +
+ + +
—
128
64
32
—
64
64
—
32
64
—
64
—
+ + +
+
+ + +
+
++
+ + +
—
++
++
—
—
++
++
—
+ + +
++
—
+
+
++
+
++
+
+ + +
+ + +
—
+ + +
++
—
++
++
+ + +
32
128
+ + +
32
128
—
—
+
+
The width of the zone of inhibition indicates the potency of antibacterial activity;
(−) no antibacterial activity; (+) mild activity with the diameter of the zones equal
to 0.6–0.8 cm; (++) moderate activity with the diameter of the zones equal to
1.2–1.3 cm; (+ + +) marked activity with the diameter of the zones equal to
1.8–2.0 cm. E. coli is Gram-negative and St. aur is a gram-positive bacteria and
Asperigllus flavus and Candida albicans as fungi.25–27
CONCLUSION
From Table III it can be seen that compounds Va, XVIa, and XXa were
the most effective against both gram-negative and gram-positive bac-
terial strains whereas some other compounds have moderate effect on
the tested bacteria, while compounds VIIa and XVIa were the most
effective against the tested fungi. We can conclude that compounds
Va, XVIa, and XXa can be used as antibacterial agents both gram-
negative and gram-positive bacteria, while compounds VIIa and XVIa
can be used as antifungi agents against Asperigllus flavus and Candida
albicans.
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