Thiosemicarbazide Derivatives as Building Block in Synthesis of Target Heterocyclic Compounds with Their Antimicrobial Assessment

Article abstract of DOI:10.1002/jhet.2719

1-(2-Benzamido-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-4-phenylthiosemicarbazide is used as precursor for synthesis of imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3-oxazine, and 1,2,4-triazine ring systems. The antimicrobial activity of some of th

Full text of DOI:10.1002/jhet.2719

Month 2016
Thiosemicarbazide Derivatives as Building Block in Synthesis of Target
Heterocyclic Compounds with Their Antimicrobial Assessment
*
Wael S. I. Abou Elmagd, Magdy M. Hemdan, Sandy S. Samy, and Ahmed S. A. Youssef
Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt
*
E-mail: waelmagd97@yahoo.com
Received March 19, 2016
DOI 10.1002/jhet.2719
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
1-(2-Benzamido-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-4-phenylthiosemicarbazide is used as precur-
sor for synthesis of imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3-oxazine, and 1,2,4-triazine ring sys-
tems. The antimicrobial activity of some of the synthesized compounds was tested.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
RESULTS AND DISCUSSION
Acylhydrazone moieties are important pharmacophoric
cores of several anti-inflammatory, anti-nociceptive, and
anti-platelet activities [1–3]. Thiosemicarbazides are valu-
able building blocks for the synthesis of different heterocy-
clic ring systems [4–6]. Their synthesis includes several
methods [7], and the method most frequently used is the re-
actions of isothiocyanates with hydrazines [8–10]. In con-
tinuation of our research in the domain of heterocyclic
synthesis [11–14] herein, we are looking forward to com-
bine acylhydrazone with phenyl isothiocyanate to get
novel thiosemicarbazide derivatives as multifunctional
compounds. Their behaviors toward different reagents
and under different media are investigated in this work.
The new derivatives of thiosemicarbazide 3a, b were
prepared by refluxing a solution of hydrazide derivatives
1a, b [4] and phenyl isothiocyanate 2 in acetonitrile as
shown in Scheme 1. The structures of the obtained prod-
ucts and those described later were confirmed on the basis
of microanalytical and spectral data (Experimental). Thus,
their multiple NH groups give rise bands in the range
3380–3128cmÀ1 in their infrared (IR) spectra. Intense
broad band at 1543–1577cmÀ1, indicative of C-N-H vibra-
tion, is regarded as combination bands due to NH-
deformation and CN stretching. Their carbonyl groups
1
produced absorption bands at 1683–1646 cmÀ1. The H
NMR spectra of compounds 3a, b are presented in the
© 2016 Wiley Periodicals, Inc.

W. S. I. Abou Elmagd, M. M. Hemdan, S. S. Samy, and A. S. A. Youssef
Vol 000
Scheme 1
Scheme 3
Experimental section and are in accordance with their pro-
posed structures. They were revealed signals corresponding
to aromatic protons in addition to those of NH protons in
the downfield region that exchangeable with D2O shake.
The higher integration value for the signals of aromatic pro-
tons, as well as the extra signals for acidic proton, is good
evidence for the existence of compound 3a as an equilib-
rium mixture of thione-thiol tautomers in the ratio 46:54.
Mass spectra of compounds 3a, b showed important frag-
ments peaks consistence with their proposed structures.
Thiosemicarbazide derivatives 3a, b is useful building
blocks for synthesis of many target heterocyclic systems.
They are open chain multifunctional compounds, and their
behaviors toward different reagents may lead to some
unexpected products. Thus, refluxing a solution of the
thiosemicarbazide derivative 3b in glacial acetic acid
afforded a mixture of oxadiazole derivative 4 and oxazolone
derivative 5 (Scheme 2). However, its refluxing in a solution
of equal amounts of acetic acid and hydrochloric acid mix-
ture gave 1,2,4-triazine derivative 6. Moreover, heating of
an ethanolic solution of 3b in the presence of hydrogen per-
oxide and hydrochloric acid is accompanied by release of
H2S gas to give oxadiazole derivative 7 in a good yield.
The spectral properties of compounds 4, 6, and 7 agree with
their proposed structures (Experimental). The structure of
oxazolone 5 was proved by admixture (m.p and mixed m.
p) and TLC with authentic sample prepared by reacting of
hippuric acid with 1, 3-diphenylpyrazole-4-carboxaldehyde
in acetic anhydride in the presence of fused sodium acetate.
The proposed mechanisms for the formation of com-
pounds 4 and 6 are illustrated in Schemes 3 and 4,
respectively. The formation of compound 7 can be visual-
ized on the basis of cyclisation of 3b via elimination of a
molecule of H2S. The release of H2S gas during the reac-
tion progress in all of the aforementioned reactions in
Scheme 2 was detected by turning the color of a paper
soaked in lead acetate solution to black.
A further aspect of reactivity of compound 3b was
exemplified by its heating with phosphoryltrichloride to
produce 1,3,4-thiadiazole derivative 8. Furthermore, the
reaction of 3b with malonic acid in the presence of acetyl
chloride gave 1,3-oxazine derivative 10. Refluxing a
solution of compound 3b in pyridine with equal amount
of o-phenylene diamine produced a mixture of amino imid-
azole derivative 11 and benzimidazole derivative 12. On
the other hand, compound 11 was obtained upon refluxing
of 3b with phenylhydrazine in ethanol or just refluxing of
3b in n-butanol (Scheme 5).
The structure of the adduct obtained from reaction of 3b
with malonic acid in the presence of acetyl chloride was
proved to be 1,3-oxazine-4,6-dione 9 on the basis of IR
spectrum that revealed bands corresponding to coupling
pattern of the two C=O groups, as well as the stretching
absorption of the methylene group. However, the 1HNMR
spectrum is devoid of any signals in the up field region
corresponding to CH2 group, instead, exhibits an ex-
changeable singlet signal in the down field region for OH
proton. This suggests its existence in deuterated
dimethylsulfoxide as hydroxyloxazine derivative 10. The
Scheme 2
Scheme 4
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Scheme 5
bacteria, Escherichia coli and Gram-positive bacteria,
Staphylococcus aureus, in addition to Aspergillus flauvs
(fungus), and Candida albicans (fungus).
O
PhN
N
O
PhN
N
ArHC
ArHC
O
O
N
N
N
O
N
O
The tested compounds 6, 7, 8, and 10 are exhibited no activ-
ity to low activity against both E. coli, S. aureus, Aspergillus
flavus (pathogenic mold), and C. albicans (pathogenic yeast).
Thus, in comparison with Ampicillin (antibacterial agent),
compounds 8 and 10 showed zone of inhibition diameters
ranged from 9 to 10 against E. coli (GÀ), and compounds 6,
8 and 10 showed zone of inhibition diameters ranged from 9
to 10 against S. aureus (G+). On the other hand, all the tested
compounds showed no activity against A. flavus and C.
albicans comparing with Amphotericin B (antifungal agent).
Ph
HO
Ph
O
9
10
N
N
acetyl chloride
malonic acid
ArHC
NHPh
S
POCl3
3b
N
Cl
8
NH2
Ph
NH2
O
Ph
H
ArHC
N
Ar =
N
S
+
N
NH2
N
N
N
H
Ph
12
11
Ph
proposed mechanisms of formation of compounds 9–12
can be explained as depicted in Scheme 6.
CONCLUSION
The structure of compound 12 was confirmed by
comparing of its m.p., mixed m.p., and TLC with a sample
prepared from heating of a mixture of o-phenylenediamine
and phenylisothiocyanate in ethanol; in addition to its IR
The title compound 3b could serve as a useful building
block for synthesis of many target heterocyclic systems. It
depends on the fact that it is an open chain multifunctional
compound. Its behavior towards different reagents is interest-
ing and sometimes unexpected.
1
and HNMR spectra.
Antimicrobial evaluation. The antimicrobial screening
of some of the synthesized compounds was carried out
using Kirby–Bauer disc diffusion method [15]. Briefly,
100μL of the tested bacteria/fungi were grown in 10μL of
fresh media until they reached a count of approximately
108 cells per mL for bacteria or 105 cells per mL for fungi
[16,17]. 100μL of microbial suspension was spread onto
agar plates corresponding to the broth in which they were
maintained. The possible antimicrobial activities of the
synthesized compounds 6, 7, 8 and 10 were investigated to
four standard organisms including the Gram-negative
EXPERIMENTAL
Melting points of the reaction products were measured in
open capillary tubes on an electrothermal melting point
apparatus and were uncorrected. The elemental analyses were
performed on a Perkin-Elemer 2400 CHN elemental analyzer
(Perkin-Elemer Company, Waltham, MA). The infrared spec-
tra were recorded on Perkin-Elemer Modle 297 Infrared
1
spectrometer using the KBr wafer technique. The H-NMR
spectra were measured on Varian Gemini 300MHz spec-
trometer, with chemical shift (δ) expressed in ppm downfield
with tetramethylsilane as internal standard, in DMSO-d6 and
coupling constants J in Hz. Mass spectra were determined on
Shimadzu GC-MSQP 1000 EX MS spectrometer (Shimadzu
Scientific Instruments, Inc., Japan) operating at 70eV at the
Micro Analytical Center of Cairo University. Thin layer
chromatography (TLC) was run using TLC aluminum sheets
silica gel F254 (Merck). It was carried out the monitoring of
the progress of all reactions and homogeneity of the synthe-
sized compounds. The antimicrobial activity was carried out
at Micro Analytical Center at Cairo University.
Scheme 6
Synthesis of the thiosemicarbazide derivatives (3a and 3b)
General procedure. A solution of phenyl isothiocyanate
2 (3mmol) and hydrazide derivatives 1a or 1b (3 mmol) in
30mL dry acetonitrile was refluxed 3 h. The resulting solid
product was collected by filtration and recrystallized from
ethanol to give the corresponding compounds 3a or 3b,
respectively.
1-(2-Benzamido-3-phenylacryloyl)-4-phenylthiosemicarbazide
(3a).
Colorless crystals (83%), m.p 142°C (with
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W. S. I. Abou Elmagd, M. M. Hemdan, S. S. Samy, and A. S. A. Youssef
Vol 000
decomposition); FTIR (KBr) cmÀ1: 3205 (NH), 3060 (aryl-
H), 1683, 1647 (CO), 1198 (CS), 691, 751 δ5H. HNMR
Pale brown crystals (63%), m.p. 208–210°C (EtOH);
FTIR (KBr) cmÀ1: 3272, 3147 (NH), 3065 (aryl-H),
2972, 2901 (alkyl-H), 1692 (C=O), 1596 (C=N), 690,
1
(DMSO-d6) δ: 6.47–8.38 (m. 32H, (30PhH +2CH=)), 10.57
(br. s, 2H, 2NHCOPh, exchangeable), 9.81 (br. s, 1H,
PhNHCS & PhNHC=N exchangeable), 9.30 (br. s, 1H,
CONH, exchangeable), for thione isomer: 5.37 (br. s, 1H,
CSNHNH, exchangeable), for thiol isomer: 4.33 (br. s, 1H,
SH, exchangeable). MS (70 eV) m/z (%): 416 (M+, 0), 386
(26), 385(M+.- SH, 21), 364 (22), 334 (33), 300 (34), 281
(22), 247 (28), 217 (29), 181 (45), 166 (7), 135 (39), 123
(50), 81 (100); Anal. Calcd for C23H20N4O2S (416.50): C,
66.33; H, 4.84; N, 13.45. Found C, 66.11; H, 4.56; N, 13.17%.
1-(2-Benzamido-3-(1,3-diphenyl-1H-pyrazole-4-yl)acryloyl)-
4- phenylthiosemicarbazide (3b). Colorless crystals (86%),
m.p 181–182°C; FTIR (KBr) cmÀ1: 3380, 3177, 3128
(NH), 3061 (aryl-H), 1683, 1646 (CO), 1191 (CS), 692,
757 δ5H
.
1HNMR (DMSO-d6) δ: 3.96 (s, 2H, CH2), 4.32 (br. s, 1H,
NHPh, exchangeable), 7.27–7.54 (m, 11H, Ph-H), 7.75 (d,
2H, J=8.1Hz), 7.87 (d, 2H, J=8.4Hz), 8.45 (s, 1H,
pyrazolo-H), 13.68 (br. s, 1H, NHCO, or OH, exchangeable).
MS (70eV) m/z (%): 420 (M+., 0), 419 (M+ -H, 0.12), 404
(2), 258 (21), 233 (18), 218 (8), 155 (17), 91 (4), 77 (21).
Anal. Calcd for C25H20N6O (420.47): C, 71.41; H, 4.79; N,
19.99. Found C, 71.66; H, 4.52; N, 19.63%.
N-(2-(1,3-diphenyl-1H-pyrazole-4-yl)-1-(5-(phenylamino)-
1,3,4-oxadiazole-2-yl) vinyl) benzamide (7). A mixture of
compound 3b (3 mmol), 5M HCl (10 mL) and 30%
hydrogen peroxide (5 mL) in ethanol (30 mL) was
refluxed for 2 h. The reaction mixture was cooled to room
temperature and then neutralized by addition of 5 M
sodium carbonate solution. A solid product was obtained,
filtered off and recrystallized to give compound 7.
Yellow crystals (72%), m.p 218–220°C (EtOH); FTIR
(KBr) cmÀ1: 3281, 3177 (NH), 3056 (aryl-H), 1697,
755 δ5H.
1HNMR (DMSO-d6) δ: 7.07–7.80 (m, 21H,
(20PhH+CH=)), 8.74 (s, 1H, pyrazolo-H), 10.55 (br. s,
1H, NHCOPh, exchangeable), 10.38 (br. s, 1H, PhNHCS,
exchangeable),
9.80
(br.s,
1H,
CONHNHCS,
exchangeable), 9.35 (br. s, 1H, CONHNHCS,
exchangeable). MS (70eV) m/z (%): 558 (M+, 0.2), 509
(1), 439 (2), 411 (2), 386 (10), 368 (21), 313 (10), 255
(13), 180 (17), 152 (19), 135 (25), 111 (34), 69 (100).
Anal. Calcd for C32H26N6O2S (558.65): C, 68.80; H, 4.69;
N, 15.04. Found C, 68.63; H, 4.47; N, 14.88%.
Reaction of the thiosemicarbazide derivative 3b with
glacial acetic acid. A solution of compound 3b (3mmol)
in acetic acid (20 mL) was refluxed for 3 h. The reaction
mixture was cooled to room temperature; a solid product
was obtained, filtered off to give compound 4. However,
evaporation of the mother liquor at room temperature
gave the oxazolone derivative 5, which was proved by m.
p, mixed m.p and TLC with authentic sample prepared
by reacting of hippuric acid with 1, 3-diphenylpyrazole-
4-carboxaldehyde in acetic anhydride in the presence of
fused sodium acetate [18].
1
1657 (C=O), 1597, 1529 (C=N), 689, 752 δ5H. HNMR
(DMSO-d6) δ: 6.97–8.18 (m, 21H, (20 Ph-H + 1CH=),
8.67 (s, 1H, pyrazolo-H), 9.31 (br. s, 1H, NHPh,
exchangeable), 10.53 (br. s, 1H, NHCOPh, exchangeable).
MS (70 eV) m/z (%): 524 (M+, 19), 509 (2), 466 (6), 431
(27), 405 (37), 346 (7), 271 (16), 119 (95), 105 (52), 91
(17), 77 (100). Anal. Calcd for C32H24N6O2 (524.57): C,
73.27; H, 4.61; N, 16.02. Found C, 73.10; H, 4.38; N,
15.88%.
5-(1-(Chloro(phenyl)methyleneamino)-2-(1,3-diphenyl-1H-
pyrazole-4-yl)vinyl)-2- phenylamino-1,3,4-thiadiazole (8).
Compound 3b (3 mmol) and phosphoryltrichloride
(15 mL) was refluxed for 1 h. The reaction mixture was
cooled to room temperature and then poured into ice/cold
water. A solid product was obtained, filtered off and
recrystallized from diethyl ether to give compound 8.
Brown crystals (76%), m.p 283–285°C (EtOH); FTIR
(KBr) cmÀ1: 3221, 3185 (NH), 3055 (aryl-H), 1640,
5-Methyl-2-phenylamino-1,3,4-oxadiazole (4). Pale green
crystals (41%), m.p 110–112°C (light petroleum ether 60–
80°C); FTIR (KBr) cmÀ1: 3293, 3260, 3194 (NH), 3079,
3060 (aryl-H), 2973, 2827 (alkyl-H), 1663, 1599 (C=N),
1600, 1565, 1499 (C =N), 691, 756 δ5H
.
1HNMR
1
694, 756 δ5H. HNMR (DMSO-d6) δ: 2.03 (s, 3H, CH3),
(DMSO-d6) δ: 6.97–8.57 (m, 21H, (20 Ph-H + 1CH=),
8.66 (s, 1H, pyrazolo-H), 10.35 (br. s, 1H, NHPh, ex-
changeable). MS (70 eV) m/z (%): 559 (M+., 22), 475
(14), 443 (35), 406 (33), 345 (100), 284 (54). 210 (92),
189 (37), 176 |(18), 116 (22). Anal. Calcd for
C32H23ClN6S (559.08): C, 68.75; H, 4.15; N, 15.03. Found
68.43; H, 3.87; N, 14.76%.
7.01 (t, 1H, J =7.5 Hz), 7.27 (t, 2H, J =7.2 Hz), 7.56 (d,
2H, J= 8.1Hz), 9.87 (br. s, 1H, NH, exchangeable). MS
(70 eV) m/z (%): 175 (M+, 0.75), 161 (0.99), 135 (15), 93
(100), 77 (7), 65 (16). Anal. Calcd for C9H9N3O
(175.19): C, 61.70; H, 5.18; N, 23.99. Found C, 61.89;
H, 4,87; N, 23.68%.
5-((1,3-Diphenyl-1H-pyrazole-4-yl)methyl)-3-(phenylamino)-
3-(4-((1,3-Diphenyl-1H-pyrazole-4-yl)methylene)-5-oxo-2-
phenyl-4,5-dihydroimid azol-1-yl)-4-hydroxy-2-(phenylimino)-
1,2,4-triazin-6(1H)-one (6).
A solution of compound 3b
(3mmol) in acetic acid (15mL) and 5M HCl (15mL) was
refluxed for 3h. The reaction mixture was cooled to room
temperature; a solid product was obtained, filtered off to
give compound 6.
2,3-dihydro-1,3-oxazin-6-one (10).
A
mixture of
compound 3b (3mmol), malonic acid (3 mmol), and
acetyl chloride (15mL) was refluxed for 1/2h. The
reaction mixture was vacuum distilled to dryness. The
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solid product that obtained was washed with water several
times and then recrystallized from light petroleum ether
60–80oC to give compound 10. Pale yellow crystals
(78%), m.p. 179–182°C; FTIR (KBr) cmÀ1: 3060 (aryl-
H), 2922 (alky-H), 1778, 1757 (C=O), 1649, 1598 (C=N),
689, 753 δ.5H1HNMR (DMSO-d6) δ: 7.16 (s, 1H,
CH=COH), 7.43–8.26 (m, 21H, (20PhH+1CH=), 9.38 (s,
1H, pyrazolo-H), 9.55 (br. s, 1H, OH, exchangeable). MS
(70eV) m/z (%): 591 (M+. - H, 0.08), 574 (0.09), 441
(0.1), 392 (4), 391 (14), 258 (5), 173 (1), 155 (2), 128 (4),
105 (100), 77 (80). Anal. Calcd for C35H24N6O4 (592.6):
C, 70.94; H, 4.08; N, 14.18. Found 70.68; H, 3.79; N,
13.91%.
as positive controls for antimicrobial activity, but filter
discs impregnated with 10μL of DMSO were used as a
negative control. The agar used is Meuller–Hinton agar.
Blank paper disks (Schleicher & Schull, Spain) with a
diameter 8.0mm were impregnated 10μL of tested
concentration of the stock solutions. When a filter paper
disc impregnated with a tested chemical is placed on agar
the chemical will diffuse from the disc into the agar. This
diffusion will place the chemical in the agar only around
the disc. The solubility of the chemical and its molecular
size will determine the size of the area of chemical
infiltration around the disc. If an organism is placed on the
agar, it will not grow in the area around the disc if it is
susceptible to the chemical, this area of no growth around
the disc is known as “zone of inhibition” of “clear zone.”
Formation of compounds 11 and 12.
An equivalent
amounts of compound 3b (3 mmol) and o-phenylene
diamine (3 mmol) were refluxed for 3 h in ethanol
(30 mL). A mixture of solid products (TLC) was obtained
after cooling that was filtered off. Heating the solid
mixture with light petroleum ether 60–80oC gives
compound 11 and leaves a residue that was recrystallized
from ethanol to give compound 12. Compound 11 was
obtained when phenyl hydrazine (3 mmol) was used
instead of o-phenylene diamine and also on refluxing of
compound 3b alone in n-butanol (20 mL).
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1-Amino-4-((1,3-diphenyl-1H-pyrazole-4-yl)methylene)-2-
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224–226°C; FTIR (KBr) cmÀ1: 3323, 3250 (NH), 3054
(aryl-H), 1706 (CO), 1635, 1597 (C=N), 691, 754
δ5H.1HNMR (DMSO-d6) δ: 5.36 (br. s, 2H, NH2,
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7.71 (d, 2H, J = 8.1 Hz), 7.97 (d, 2H, J =8.7 Hz), 8.44 (d,
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1H-Benzo[d]imidazole-2(3H)-thione (12).
Colorless
(17)
crystals m.p. 293–294°C (Lit.
m.p 282–284°C)
(Ethanol); FTIR (KBr) cmÀ1: 3153, 3114 (NH), 1355
1
(C=S). HNMR (DMSO-d6) δ: 7.08–7.15 (m, 4H), 12.48
(br. s, 2H, NH, exchangeable).
Assessment of the antimicrobial activity using Kirby–
Bauer method. Plates inoculated with filamentous fungi
as Aspergillus fluvs at 25°C for 48h; Gram-positive
bacteria, as S.aureus; Gram-negative bacteria as E.coli
o
they were incubated at 35–37 C for 24–48h and yeast as
C.albicans incubated at 30°C for 24–48h and then the
diameters of the inhibition zones were measured in
millimeters. Standard discs of Ampicillin (antibacterial
agent), and Amphotericin B (antifungal agent) were served
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet