Ring transformation and antimicrobial activity of indolyl-substituted 2(3H)-furanones

Article abstract of DOI:10.1515/hc-2015-0008

A variety of heterocycles of synthetic and biological importance were prepared from 3-(indol-3-yl-methylene)-5-phenyl-2(3H)-furanone (1) and its hydrazide 2. Compounds 1 and 2 were used for the construction of pyridazin-3(4H)-ones 4 and 6; 1,3,4-oxadiazoles 7, 8, and 10; and 1,2,4-triazoles 12, 14, and 15, all bearing a 3-indolyl moiety. The antimicrobial activities of the synthesized compounds were examined against six types of bacteria and two types of fungi.

Full text of DOI:10.1515/hc-2015-0008

Heterocycl. Commun. 2015; aop
Wael S.I. Abou-Elmagd, Ahmed K. EL-Ziaty and Abdelaal A. Abdalha*
Ring transformation and antimicrobial activity of
indolyl-substituted 2(3H)-furanones
Abstract: A variety of heterocycles of synthetic and bio- 1,2,4-Triazoles are broad-spectrum antifungal agents used
logical importance were prepared from 3-(indol-3-yl- as pesticides and pharmaceuticals. They inhibit the bio-
methylene)-5-phenyl-2(3H)-furanone (1) and its hydrazide synthesis of ergosterol, which is an essential component
2. Compounds 1 and 2 were used for the construction of of fungal membranes [29, 30].
pyridazin-3(4H)-ones 4 and 6; 1,3,4-oxadiazoles 7, 8,
These reported diverse biological activities prompted
and 10; and 1,2,4-triazoles 12, 14, and 15, all bearing a us to attempt the conversion of furanone 1 into pyri-
3-indolyl moiety. The antimicrobial activities of the syn- dazinones, 1,3,4-oxadiazoles, and 1,2,4-triazoles, all
thesized compounds were examined against six types of bearing an indolyl moiety. Some of the obtained products
bacteria and two types of fungi.
were evaluated for their antimicrobial activity.
Keywords: 2(3H)-furanone; indole; oxadiazole; pyri-
dazinone; triazole.
Results and discussion
DOI 10.1515/hc-2015-0008
The 2(3H)-furanone 1 has previously been prepared by
one of us [3]. Hydrazide 2 has previously been prepared
[4] via treating furanone 1 with hydrazine hydrate. In this
work, pyridazinone 4 was synthesized by ring closure of
benzohydrazide 3, which was obtained by the reaction of
Received January 17, 2015; accepted March 27, 2015
Introduction
O
X
O
2(3H)-Furanones are key starting materials for the con-
struction of many heterocyclic systems [1–16]. The key
step in these transformations is the formation of the acid
hydrazides, which are formed by the action of hydrazine
hydrate on the furanones.
Indole-substituted compounds are common in nature
[17]; one of the most important and simple derivatives
is the amino acid tryptophan. Pyridazinones have been
reported to possess antimicrobial [18], analgesic [19],
anti-inflammatory [20], antidiabetic [21], herbicidal [22],
antihypertensive [23], anticancer [24], antifungal [25],
and other pharmacological properties [26]. Compounds
containing 1,3,4-oxadiazole moiety have a broad bio-
logical spectrum. Two examples of compounds currently
used in clinical medicine are raltegravir, an antiretrovi-
ral drug [27], and zibotentan, an anticancer agent [28].
Benzoylhydrazine
O
X
O
HN NH
Ph
Ph
1
Ph
3
O
Hydrazine
HCl/AcOH
Benzoyl
chloride
O
X
O
O
X
NH
HN NH2
N
Ph
Ph
2
Ph
O
O
Naphthoyl
chloride
4
X
O
O
H
X
NH
N
HN
N
O
HCl/AcOH
Ph
Ph
O
5
6
*Corresponding author: Abdelaal A. Abdalha, Faculty of Science,
Chemistry Department, Ain Shams University, Abassia, Cairo 11566,
Egypt; and Chemistry Department, Tabuk University, Tabuk, KSA,
e-mail: abdoelaal@yahoo.com
Wael S.I. Abou-Elmagd and Ahmed K. EL-Ziaty: Faculty of Science,
Chemistry Department, Ain Shams University, Abassia, Cairo 11566,
Egypt
X =
N
H
Scheme 1:ꢀSynthesis of pyridazinone derivatives.
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2ꢀ
ꢀW.S.I. Abou-Elmagd et al.: Indolyl-substituted 2(3H )-furanones
O
O
O
H
H
N
NH2
N
O
X
N
H
CHO
X
N
H
X
N
H
HCOOH
PhCOCl
Ph
Ph
Ph
Ph
9
2
3
O
O
O
POCl3
P2O5
N
CS2/NaOH/EtOH
X =
N
H
NH
N
N
O
N
N
S
Ph
O
O
X
X
X
Ph
Ph
Ph
10
8
7
O
O
O
Scheme 2:ꢀSynthesis of 1,3,4-oxadiazole derivatives.
acid hydrazide 2 with benzoyl chloride. The structure of 3 for 10 h yielded N-formyl derivative 9, which was easily
was supported by comparison with an authentic sample cyclized through dehydration by heating with phosphorus
prepared by the treatment of furanone 1 with benzoyl pentoxide in dry toluene to give 1,3,4-oxadiazole deriva-
hydrazine. The treatment of hydrazide 2 with naphthoyl tive 10 (Scheme 2). The structures of compounds 7–10
chloride afforded naphthohydrazide derivative 5. Ring were elucidated from their analytical and spectroscopic
closure of 5 by using HCl/AcOH (1:1) mixture afforded data. The treatment of hydrazide 2 with potassium iso-
N-napthopyridazinone derivative 6 (Scheme 1). The struc- thiocyanate afforded thiosemicarbazide derivative 11,
tures of 3–6 are in full agreement with their analytical and which was also formed by the reaction of furanone 1 with
spectral data.
thiosemicarbazide. Ring closure of 11 in 2N NaOH yielded
The treatment of benzohydrazide derivative 3 with triazolethione derivative 12. Semicarbazide derivative 13
phosphorus oxychloride yielded 1,3,4-oxadiazole deriva- was also prepared by the reaction of hydrazide 2 with
tive 7. Oxadiazolethione derivative 8 was obtained when potassium isocyanate and/or treatment of furanone 1 with
hydrazide 2 was allowed to react with carbon disulfide semicarbazide hydrochloride/sodium acetate mixture.
in refluxing alcoholic sodium hydroxide. By contrast, the Triazolone derivative 14 was prepared by ring closure of
treatment of hydrazide 2 with formic acid under reflux semicarbazide derivative 13 using 2N NaOH. By contrast,
O
O
O
H
H
N
O
N
S
Semicarbazide
CH3COONa
Thiosemicarbazide
X
X
N
X
N
H
O
H
Ph
NH2
Ph
NH2
Ph
13
1
11
O
O
2N NaOH
NH
Hydrazine
O
2N NaOH
NH
KNCS
KNCO
N
N
O
S
NH2
N
N
H
N
X
X
X
H
H
Ph
Ph
Ph
14
2
12
O
O
O
PhNCS
NH
N
S
N
Ph
X
X =
Ph
N
H
15
O
Scheme 3:ꢀSynthesis of 1,2,4-triazole derivatives.
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W.S.I. Abou-Elmagd et al.: Indolyl-substituted 2(3H)-furanonesꢂ ꢂ3
hydrazide 2 was allowed to react with phenyl isothiocy- gram-positive bacteria (Staphylococcus aureus, Bacillus
anate in sodium hydroxide (10%) followed by acidification subtilis, Bacillus cereus, and Kocuria rhizophila), two types
to yield 4-phenyltriazolethione derivative 15 (Scheme 3). of gram-negative bacteria (Salmonella typhimurium and
The structures of compounds 11–15 were confirmed by the Escherichia coli), and two fungus (yeast Candida albicans
analysis of the analytical and spectroscopic data.
and mould Aspergillus niger); novobiocin, chlorampheni-
The synthesized compounds were evaluated for col, and nystatin were used as standard drugs for antibac-
their in vitro antimicrobial activity using four types of terial and antifungal activities (Tables 1–3). The results
Table 1:ꢀAntibacterial and antifungal activities (as inhibition zone in mm diameter).
Compound
ꢁ
Staphylococcus
aureus
ꢁ
Kocuria
rhizophila
ꢁ
Salmonella
typhimurium
ꢁ Escherichia
ꢁ Candida
albicans
ꢁ Aspergillus
coli
niger
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
20
22
20
17
21
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
15
24
19
11
20
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
11
14
16
13
14
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
11
15
12
10
13
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
12
15
13
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
0
0
4
11
0
13
0
0
13
15
0
0
0
14
0
12
13
14
0
0
14
15
0
0
0
0
Novobiocin
23
23
0
22
21
0
10
17
0
11
17
0
Chloramphenicolꢃ
Nystatin
ꢃ
Table 2:ꢀMIC (μg/mL) for the active compounds.
Compound
ꢁ
Staphylococcusꢁ
Kocuriaꢁ
rhizophila
Salmonellaꢁ
typhimurium
Escherichiaꢁ
Candida
albicans
aureus
coli
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
30ꢃ
0ꢃ
25ꢃ
50ꢃ
30ꢃ
50ꢃ
30ꢃ
0ꢃ
30ꢃ
60ꢃ
25ꢃ
60ꢃ
30ꢃ
0ꢃ
50ꢃ
60ꢃ
30ꢃ
70ꢃ
25ꢃ
0ꢃ
60
50
25
0
4
11
25ꢃ
50ꢃ
30ꢃ
0ꢃ
13
14
0
12
60
30
0
0
40
15
0ꢃ
0ꢃ
0ꢃ
0ꢃ
Novobiocin
30ꢃ
30ꢃ
0ꢃ
25ꢃ
25ꢃ
0ꢃ
60ꢃ
30ꢃ
0ꢃ
50ꢃ
30ꢃ
0ꢃ
Chloramphenicolꢃ
Nystatin
ꢃ
Table 3:ꢀMinimum bactericidal concentration (MBC, μg/mL) for active compounds.
Compound
ꢁ
Staphylococcus
aureus
ꢁ
Kocuria
rhizophila
ꢁ
Salmonella
typhimurium
ꢁ Escherichia
ꢁ Candida
albicans
coli
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
80
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
70
70
70
80
50
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
80
100
90
100
100
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
70
110
130
100
50
0
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
110
70
50
0
4
11
50
50
60
0
13
14
0
12
120
60
0
0
50
15
0
0
0
0
Novobiocin
50
40
0
50
40
0
100
50
0
100
50
0
Chloramphenicolꢃ
Nystatin
ꢃ
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ꢀꢀꢀꢁ
4ꢀ ꢀW.S.I. Abou-Elmagd et al.: Indolyl-substituted 2(3H )-furanones
(d, 1H, J ꢀ=ꢀ 7.2 Hz), 3.42 (d, 1H, J ꢀ=ꢀ 7.2 Hz), 6.69–7.59 (m, 16H), 8.92 (s,
1H), 11.78 (br s, 2H); 13C NMR: δ 38.8, 111.1, 111.9, 119.7, 120.1, 121.9,
122.2, 127.5, 127.9, 128.3, 128.7, 129.1, 130.8, 132.3, 133.2, 134.9, 135.2,
revealed that the majority of the synthesized compounds
show varying degrees of inhibition against the tested
microorganisms. Only pyridazinones and triazoles show
significant antimicrobial activities. More specifically,
compounds 1, 4, and 11–15 exhibit high antibacterial and
antifungal activities compared with the standard drugs,
whereas compounds 2, 6–8, and 10 exhibit no antimicro-
bial activity.
+
136.1, 138.3, 164.9, 165.7, 194.7; MS m/z (%): 423 (M , 15), 330 (100),
299 (27), 271 (29), 167 (32), 104 (44), 77 (48). Anal. Calcd for C26H21N3O3:
C, 73.74; H, 5.00; N, 9.92. Found: C, 73.98; H, 4.93; N, 9.73.
Synthesis of N-[2-((1H-indol-3-yl) methylene)-4-oxo-
4-phenylbutanoyl]naphthohydrazide (5)
Naphthoyl chloride (10 mmol) was added to a solution of hydrazide 2
(10 mmol) in dry benzene (20 mL). The reaction mixture was heated
under reflux for 3 h. The solvent was distilled under reduced pres-
sure, and the deposited solid was filtered, washed several times with
cold water, dried, and then recrystallized from ethanol to give com-
Conclusion
A series of novel pyridazinones,1,3,4-oxadizole, and
1,2,4-triazole derivatives has been synthesized using a
facile strategy and screened for antimicrobial activities.
Some of the prepared compounds exhibit high antibacte-
rial and antifungal activities compared with the standard
drugs.
pound 5 in 65% yield as colorless crystals; mp 240–242°C; IR (νmax
,
1
cm-1): 3295, 3215, 3120 (NH), 1692, 1645 (Cꢀ=ꢀO); HNMR: δ 3.19 (d, 1H,
J ꢀ=ꢀ 7.2 Hz), 3.22 (d, 1H, J ꢀ=ꢀ 7.2 Hz), 6.55–8.17 (m, 18H), 8.86 (s, 1H),
11.21 (br s, 2H,); 13C NMR: δ 39.7, 110.6, 111.7, 119.0, 120.2, 120.5, 122.5,
126.1, 127.3, 127.4, 128.5, 128.8, 129.5, 130.3, 130.9, 131.8, 132.3, 133.7,
134.1, 134.4, 134.7, 135.2, 135.5, 136.8, 138.5, 165.7, 166.9, 194.3. MS, m/z
+
(%): 473 (M , 18), 371 (21), 339 (22), 177 (22), 99 (27), 69 (28), 57 (100).
Anal. Calcd for C30H23N3O3: C, 76.09; H, 4.90; N, 8.87. Found: C, 76.28;
H, 4.95; N, 9.01.
Experimental
Uncorrected melting points were measured on a Gallen Kamp elec-
tric melting point apparatus. Infrared spectra were recorded using
potassium bromide disks on FTIR Thermo Electron Nicolet 7600
(USA) infrared spectrometer at the central laboratory of Faculty
General method for ring closure of benzohydrazides 3
and 5 using HCl/AcOH
1
of Science, Ain Shams University. H-NMR (300 MHz) and 13C-NMR
A solution of 3 or 5 (1 g) in a mixture of HCl/AcOH, 1:1 (30 mL), was
heated under reflux for 1 h and then cooled. The resultant solid was
filtered, washed with water, and crystallized from ethanol to give the
respective product 4 or 6.
(75 MHz) spectra were measured in DMSO-d6 on a Varian plus instru-
ment. Mass spectra were recorded on a Shimadzu GC-MS QP-1000EX
mass spectrometer operating at 70 eV at the Micro Analytical Center
of Cairo University. The progress of all reactions was monitored by
thin layer chromatography using Merck Kiesel gel 60 F254 aluminum-
backed plates. The spots were developed using a UV lamp.
Antimicrobial activity was conducted at El-Rashidi Elmizan
Confectionery Company, 2nd industrial zone, 6th of October City,
Cairo, Egypt, and Regional Center for Mycology and Biotechnology
(RCMB), Al-Azhar University.
4-[(1H-Indol-3-yl)methylene]-1-benzoyl-6-phenyl-1,2-dihydro-
pyridazin-3(4H)-one (4)ꢁThis compound was obtained in 80%
yield as colorless crystals; mp 136–138°C; IR (νmax, cm-1): 3297, 3115
1
(NH), 1667, 1650 (Cꢀ=ꢀO); H NMR: δ 6.20 (s, 1H), 6.50–8.59 (m, 16H),
8.90 (s, 1H), 10.11 (br s, 1H); 13C NMR: δ 84.3, 110.7, 112.4, 119.6, 121.4,
122.2, 126.5, 126.9, 127.9, 128.1, 128.7, 128.9, 131.1, 132.3, 133.9, 134.4,
+
135.6, 135.9, 136.8, 139.7, 149.4, 169.9; MS m/z (%): 405 (M , 20), 382
(18), 330 (100), 299 (27), 286 (21), 271 (29), 155 (33), 104 (44), 77 (45),
59 (26). Anal. Calcd for C26H19N3O2: C, 77.02; H, 4.72; N, 10.36. Found:
C, 77.17; H, 4.55; N, 10.78.
Synthesis of N-[2-((1H-indol-3-yl)methylene)-4-oxo-
4-phenylbutanoyl]benzohydrazide (3)
Benzoyl chloride (10 mmol) was added to a solution of hydrazide 2
(10 mmol) in dry benzene (20 mL). The reaction mixture was heated
under reflux for 3 h. The solvent was distilled under reduced pres-
sure, and the deposited solid was filtered, washed several times with
cold water, dried, and then crystallized from ethanol to give com-
pound 3. The same product 3 was obtained by heating a solution
of furanone 1 (10 mmol) in ethanol (20 mL) with benzoyl hydrazine
(10 mmol) under reflux for 2 h. The solvent was evaporated, and the
solid residue was filtered, dried, and then crystallized from ethanol
to give compound 3 in 60% yield as colorless crystals; mp 230–231°C;
IR (νmax, cm1): 3321, 3255, 3195 (NH), 1692, 1658 (Cꢀ=ꢀO); 1HNMR: δ 3.15
4-((1H-Indol-3-yl)methylene)-1-(1-naphthoyl)-6-phenyl-1,2-di-
hydropyridazin-3(4H)-one (6)ꢁThis compound was obtained in
70% yield as colorless crystals; mp 163–165°C; IR (νmax, cm-1): 3301,
1
3212 (NH), 1662, 1653 (Cꢀ=ꢀO); H NMR: δ 7.17 (s, 1H.), 7.20–8.43 (m,
18H), 8.82 (s, 1H), 10.21 (br s, 1H); 13C NMR: δ 80.7, 110.6, 111.5, 119.6,
120.3, 122.2, 124.5, 126.1, 126.3, 126.5, 126.9, 127.9, 128.3, 128.5, 128.7,
128.9, 130.3, 130.9, 132.3, 133.5, 133.9, 134.3, 135.1, 135.9, 139.4, 139.9,
+
149.6, 169.7; MS m/z (%): 455 (M , 12), 354 (20), 330 (21), 279 (20),
177 (27), 151 (21), 99 (27), 69 (28),57 (100), 55 (38). Anal. Calcd for
C30H21N3O2 (455): C, 79.10; H, 4.65; N, 9.22. Found: C, 79.23; H, 4.39;
N, 9.40.
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was filtered, washed several times with water, dried, and crystallized
from ethanol to give compound 10 in 60% yield as pale yellow powder;
mp 230–233°C; IR (υmax, cm-1): 3242 (NH), 1655 (CO); 1HNMR: δ 3.10 (d,
Synthesis of 4-(1H-indol-3-yl)-1-phenyl-3-(5-phenyl-
1,3,4-oxadiazol-2-yl)but-3-en-1-one (7)
1H, J ꢀ=ꢀ 7.0 Hz), 3.15 (d, 1H, J ꢀ=ꢀ 7.0 Hz), 7.02–8.14 (m, 12H), 8.93 (s, 1H); 13
C
Phosphorus oxychloride (10 mL) was added dropwise to 1 g of
diaroylhydrazine 3. The reaction mixture was heated under reflux for
20 min, then cooled and poured onto crushed ice. The resultant solid
was filtered, washed with water, and crystallized from ethanol to give
compound 7 in 40% yield as pale yellow powder; mp 178–180°C; IR
NMR: δ 42.3, 110.6, 111.3, 119.0, 120.1, 126.3, 126.7, 127.5, 128.7, 129.8, 130.3,
+
133.2, 135.9, 140.3, 155.9, 157.2, 194.1; MS m/z (%): 329 (M , 56), 171 (27),
145 (45), 129 (100), 117 (64), 105 (30), 88 (41). Anal. Calcd for C20H15N3O2:
C, 72.94; H, 4.59; N, 12.76. Found: C, 72.77; H, 4.43; N, 12.57.
1
(νmax, cm-1): 3312 (NH), 1671 (Cꢀ=ꢀO); H NMR: δ 3.15 (d, 1H, J ꢀ=ꢀ 7.0 Hz),
3.25 (d, 1H, J ꢀ=ꢀ 7.0 Hz), 7.40–8.20 (m, 16H), 8.84 (s, 1H); 13C NMR: δ
43.6, 110.6, 111.3, 119.0, 120.1, 121.7, 126.3, 126.7, 127.5, 128.1, 128.3, 128.7,
129.8, 130.3, 133.2, 135.9, 136.4, 140.3, 164.3, 164.7, 193.9; MS m/z (%):
Synthesis of thiosemicarbazide 11 and semicarbazide 13
A solution of potassium thiocyanate or potassium cyanate (12 mmol)
in water (10 mL) was added dropwise with stirring at 0°C to a solu-
tion of hydrazide 2 (10 mmol) in AcOH/H2O (1:1 by volume) mixture.
The reaction mixture was stirred at room temperature for 3 h. The
product obtained was filtered, washed thoroughly with water, and
finally recrystallized from ethanol/dioxane mixture to give thiosemi-
carbazide 11 (from thiocyanate) and semicarbazide 13 (from cyanate).
The same product 11 was also obtained by heating under reflux
a solution of 2(3H)-furanone 1 (10 mmol) in ethanol (30 mL) with thio-
semicarbazide (10 mmol) for 1 h. Heating 1 (10 mmol) with a mixture
of semicarbazide hydrochloride (10 mmol) and anhydrous sodium
acetate (10 mmol) for 1 h gave product 13. The solid obtained was
filtered, washed thoroughly with water, and recrystallized to give
compounds 11 and 13, respectively.
+
405 (M , 67), 171 (28), 145 (20), 129 (100), 117 (14), 105 (71), 88 (41), 76
(55). Anal. Calcd for C26H19N3O2: C, 77.02; H, 4.72; N, 10.36. Found: C,
77.37; H, 4.78; N, 10.73.
Synthesis of 4-(1H-indol-3-yl)-1-phenyl-3-(5-thioxo-4,
5-dihydro-1,3,4-oxadiazol-2-yl)but-3-en-1-one (8)
Carbon disulfide (10 mL) was added to a solution of hydrazide
2 (10 mmol) in 10% alcoholic NaOH (3 g NaOH in 30 mL ethanol)
whereby the reaction mixture became brown. The mixture was
heated under reflux for 2 h, then cooled and poured onto ice-cold
water. Acidification with concentrated HCl gave a yellow precipitate,
which was filtered and crystallized from ethanol to give compound
8 in 80% yield as yellow powder; mp 218–220°C; IR (νmax, cm-1):
3273, (NH), 1666 (Cꢀ=ꢀO); 1H NMR: δ 3.35 (d, 1H, J ꢀ=ꢀ 7.2 Hz), 3.93 (d, 1H,
J ꢀ=ꢀ 7.2 Hz), 6.94–7.66 (m, 11H), 9.13 (s, 1H), 13.12 (br s, 1H); 13C NMR:
δ 35.4, 110.9, 113.4, 119.6, 120.3, 122.2, 126.5, 128.7, 128.9, 131.1, 133.2,
1-[2-((1H-Indol-3-yl)methylene)-4-oxo-4-phenylbutanoyl]thio-
semicarbazide (11)ꢁThis compound was obtained in 50% yield as
colorless crystals; mp 159–160°C; IR (υmax, cm-1): 3325, 3216, 3195, 3117
1
(NH), 1677, 1640 (Cꢀ=ꢀO), 1252 (Cꢀ=ꢀS); HNMR: δ 3.22 (s, 2H), 6.99–7.86
(m, 11H), 8.63 (s, 1H), 11.40 (br s, 1H), 11.63 (br s, 2H), 12.09 (br s, 1H);
+
134.1, 134.4, 135.6, 136.4, 160.1, 165.6, 196.5; MS m/z (%): 361 (M , 76),
13C NMR: δ 39.3, 110.7, 111.3, 119.1, 120.3, 122.2, 126.3, 128.3, 128.9, 130.3,
259 (16), 219 (23), 173 (16), 105 (36), 76 (45), 51 (100). Anal. Calcd for
C20H15N3O2S (361): C, 66.46; H, 4.18; N, 11.63; S, 8.87. Found: C, 66.62;
H, 4.23; N, 11.50; S, 8.65.
+
133.5, 135.3, 135.7, 136.9, 138.3, 165.3, 182.5, 194.3; MS m/z (%): 378 (M ,
11), 181 (78), 153 (32), 148 (38), 120 (84), 106 (38), 93 (100), 77 (88), 66
(47). Anal. Calcd for C20H18N4O2S: C, 63.47; H, 4.79; N, 14.80; S, 8.47.
Found: C, 64.12; H, 4.53; N, 15.03; S, 8.87.
Synthesis of 2-[(1H-indol-3-yl)methylene]-N-formyl-4-
oxo-4-phenyl butane hydrazide (9)
1-[2-((1H-indol-3-yl)methylene)-4-oxo-4-phenylbutanoyl]semi-
carbazide (13)ꢁThis compound was obtained in 56% yield as color-
less crystals; mp 200–202°C; IR (υmax, cm-1): 3320, 3212, 3170, 3110
(NH), 1677, 1630 (Cꢀ=ꢀO); 1H NMR: δ 3.20 (s, 2H), 7.03–7.97 (m, 11H), 8.52
(s, 1H), 11.97 (br.s, 2H), 12.86 (br s, 2H); 13C NMR: δ 38.7, 110.3, 111.1,
119.3, 120.6, 121.7, 126.1, 127.9, 128.2, 130.1, 134.9, 135.1, 136.3, 138.0,
A solution of 2 (1 g) in formic acid (10 mL) was heated under reflux.
The deposited solid during heating afer 7 h was filtered, washed sev-
eral times with water, dried, and then recrystallized from dioxane to
give compound 9 in 50% yield as colorless crystals; mp 256–257°C; IR
(ν max, cm-1): 3320, 3255, 3170 (NH), 1710, 1672, 1650 (Cꢀ=ꢀO); 1H NMR: δ
3.18 (d, 1H, J ꢀ=ꢀ 7.0 Hz), 3.25 (d, 1H, J ꢀ=ꢀ 7.0 Hz), 6.89–8.45 (m, 11H), 8.60
(s, 1H), 9.05 (s, 1H), 10.1 (br s, 1H), 10.5 (s, 1H); 13C NMR: δ 39.8, 110.9,
111.9, 119.7, 120.1, 122.2, 126.5, 127.9, 128.3, 131.1, 133.8, 135.3, 135.7, 136.9,
+
158.1, 165.1, 193.7; MS, m/z (%): 362 (M , 9), 186 (42), 257 (21), 154 (35),
127 (24), 117 (34), 104 (53), 93 (46), 77 (100), 65 (38), 51 (46). Anal.
Calcd for C20H18N4O3: C, 66.29; H, 5.01; N, 15.46. Found: C, 66.07; H,
4.92; N, 15.10.
+
138.3, 165.1, 166.7, 195.1; MS m/z (%): 347 (M , 21), 204 (56), 173 (85),
Synthesis of triazol-5-thione 12 and triazol-5-one 14
145 (100), 117 (22), 105 (76), 90 (87), 76 (50), 55 (45). Anal. Calcd For
C20H17N3O3 (347): C, 69.15; H, 4.93; N, 12.10. Found: C, 69.47; H, 4.73;
N, 12.37.
A solution of 2N NaOH (40 mL) was added to thiosemicarbazide 11
(10 mmol) or semicarbazide 13 (10 mmol). The reaction mixture was
heated under reflux for 2 h, filtered while hot, acidified with ice-cold
HCl, and diluted with 100 mL of water. The solid obtained was fil-
tered, washed with water, and crystallized from ethanol to give tria-
zol-5-thione 12 or triazol-5-one 14, respectively.
Synthesis of 4-(1H-indol-3-yl)-3-(1,3,4-oxadiazol-2-yl)-
1-phenyl but-3-en-1-one (10)
A mixture of compound 9 (1 g) and phosphorus pentoxide (1 g) in dry 3-(1-(1H-Indol-3-yl)-4-oxo-4-phenylbut-1-en-2-yl)-5-thioxo-4,5-
toluene (20 mL) was heated under reflux for 3 h. The deposited solid dihydro-1,2,4-triazole (12)ꢁThis compound was obtained in 70%
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ꢀꢀꢀꢁ
6ꢀ ꢀW.S.I. Abou-Elmagd et al.: Indolyl-substituted 2(3H )-furanones
yield as colorless crystals; mp 204–206°C; IR (υmax, cm-1): 3302, 3213,
3125 (NH), 1663 (Cꢀ=ꢀO); 1HNMR: δ 3.23 (s, 2H), 6.75–8.02 (m, 11H), 9.30
(s, 1H), 12.98 (br s, 2H);13C NMR: δ 35.3, 110.7, 111.1, 119.7, 120.1, 121.9,
126.2, 128.3, 128.7, 130.8, 132.3, 133.2, 134.9, 135.2, 136.9, 156.1, 189,
Acknowledgments: The authors acknowledge the
El-Rashidi Elmizan Confectionery Company, Cairo, Egypt,
and the Regional Center for Mycology and Biotechnology
(RCMB), Al-Azhar University, for their help in determining
biological activity.
+
194.3; MS m/z (%): 360 (M , 35), 310 (49), 293 (51), 187 (51), 117 (52), 84
(58), 58 (100). Anal. Calcd for C20H16N4OS: C, 66.65; H, 4.47; N, 15.54; S,
8.90. Found: C, 66.92; H, 4.32; N, 15.13; S, 8.77.
3-(1-(1H-Indol-3-yl)-4-oxo-4-phenylbut-1-en-2-yl)-5-oxo-4,5-
dihydro-1,2,4–triazole (14)ꢁThis compound was obtained in 74%
yield as colorless crystals; mp 234–237°C; IR (υmax, cm-1): 3302, 3218,
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1
3184 (NH), 1665, 1634 (Cꢀ=ꢀO); H NMR: δ 3.28 (s, 2H), 6.97–8.03 (m,
11H), 9.23 (s, 1H), 12.53 (br s, 2H); 13C NMR: δ 33.6, 110.3, 111.5, 119.1,
119.9, 121.7, 126.3, 128.3, 128.7, 130.8, 132.8, 133.1, 134.9, 135.5, 136.8,
+
156.3, 163, 194.7; MS m/z (%): 344 (M ,7), 285 (69), 257 (77), 242 (44),
154 (35), 127 (41), 104 (37), 91 (28), 77 (100), 65 (88), 51 (35). Anal.
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A mixture of 2 (10 mmol) and phenyl isothiocyanate (1.6 mL,
10 mmol) in (10%) sodium hydroxide (20 mL) was heated under
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1
3312, 3214, 3184 (NH), 1677 (Cꢀ=ꢀO); H NMR: δ 3.32 (s, 2H), 6.62–7.99
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+
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All microorganisms were kindly provided from the culture collection
of the Regional Center for Mycology and Biotechnology (RCMB), Al-
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of cold distilled water and then by heating to 60–70°C with stirring.
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ꢂ7
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