Reaction of hydrazonoyl halides 52:1 synthesis and antimicrobial activity of some new pyrazolines and 1,3,4-thiadiazolines

Article abstract of DOI:10.1080/10426500701313938

[5-Substituted 2-(3-phenyl-5-substituted 2-pyrazolinyl)(1,3-thiazol-4-yl)] phenyldiazene and 2,3-dihydro-1,3,4-thiadiazoles were synthesized via reactions of hydrazonoyl halides with 5-substituted-3-phenyl-4,5-dihydropyrazole-1- carboximidothionic acid an

Full text of DOI:10.1080/10426500701313938

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Reaction of Hydrazonoyl
Halides 52: Synthesis and
Antimicrobial Activity of Some
New Pyrazolines and 1,3,4-
Thiadiazolines
Abdou O. Abdelhamid a & Abdelwahed R. Sayed b
a Department of Chemistry, Faculty of Science, Cairo
University, Giza, Egypt
b Department of Chemistry, Faculty of Science, Beni-
Suef University, Beni-Suef, Egypt
Version of record first published: 15 Jun 2007.
To cite this article: Abdou O. Abdelhamid & Abdelwahed R. Sayed (2007): Reaction of
Hydrazonoyl Halides 52: Synthesis and Antimicrobial Activity of Some New Pyrazolines
and 1,3,4-Thiadiazolines, Phosphorus, Sulfur, and Silicon and the Related Elements,
182:8, 1767-1777
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Phosphorus, Sulfur, and Silicon, 182:1767–1777, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701313938
Reaction of Hydrazonoyl Halides 52:1 Synthesis
and Antimicrobial Activity of Some New Pyrazolines
and 1,3,4-Thiadiazolines
Abdou O. Abdelhamid
Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
Abdelwahed R. Sayed
Department of Chemistry, Faculty of Science, Beni-Suef University,
Beni-Suef, Egypt
[5-Substituted 2-(3-phenyl-5-substituted 2-pyrazolinyl)(1,3-thiazol-4-yl)] phenyl-
diazene and 2,3-dihydro-1,3,4-thiadiazoles were synthesized via reactions of
hydrazonoyl halides with 5-substituted-3-phenyl-4,5-dihydropyrazole-1-carboxi-
midothionic acid and {[2-2-{aza-2-((methylthioxomethyl)-amino]-vinyl}phenyl)-
1-azavinyl]amino}methylthiomethane-1-thione, respectively. All structures of the
newly synthesized compounds were elucidated by elemental analysis, spectral data,
X-ray single crystal, and alternative synthesis methods whenever possible. Some of
the new compounds were tested towards bacteria. In general, all tested compounds
were capable of a high inhibiting the growth of gram positive and gram negative.
Keywords 2,3-Dihydro-1,3,4-thiadiazoles; arylazothiazoles; hydrazonoyl halides; pyra-
zolines
INTRODUCTION
Thiosemicarbazones and its derivatives have attracted considerable
pharmaceutical interest due to their antiviral,2 antibacterial,3−5
and antitumer activities.6−12 In continuation of our work,13−16
we report herein the reactivity of hydrazonoyl halides towards
5-substituted-3-phenyl-4,5-dihydropyrazole-1-carboximidothionic acid
and {[2-2-{aza-2-[(methylthioxomethyl)-amino]-vinyl}phenyl)-1-aza-
vinyl] amino}methylthiomethane-1-thione.
Received January 5, 2006; accepted February 3, 2007.
Address correspondence to Abdou Abdelhamid, Department of Chemistry, Faculty of
Science, Cairo University, Giza 12316, Egypt. E-mail: abdou abdelhamid@yahoo.com
1767

1768
A. O. Abdelhamid and A. R. Sayed
RESULTS AND DISCUSSION
C-Acetyl-N-phenylhdrazonoyl chloride (1a) was reacted with thiosemi-
carbazide (2) and 1-phenyl-3-(2-thienyl)prop-2-ene-1-one (3a) in
ethanolic triethylamine gave one isolable product according to TLC.
The product seemed to be one of the structures 4a–7a (Scheme 1). Its IR
SCHEME 1
spectrum revealed bands at 3048 (CH), 1532 (C=C) and no absorption
band between 1650—1800, due the absence of CO group, 1H NMR spec-
trum showed signals at δ = 2.58 (s, 3H, CH3), 3.66 (dd, 1H, CH2(pyraz)),
4.01 (dd, 1H, CH(pyraz)), 6.15 (d, 1H, CH2(pyraz)), and 7.00–7.82 (m, 13H,
ArH’s and thiophene protons) and its X-Ray single crystal showed in
Figure 1. Foregoing data the product formulated as [5-methyl-2-(3-
phenyl-5-(2-thienyl)(2-pyrazolinyl))(thiazol-4-yl)]phenyldiazene (7a).
Also, compound 7a was elucidated by alternative synthesis. Thus,
compound 8b, which prepared from 2 and 3b, was reacted with 1a
or reaction of 9a, which prepared from 1a and 2, with 1-phenyl-3-(2-
thienyl)prop-2-ene-1-one (3a) gave, in each case, product identical in all
respects (mp., mixed mp., and spectra ) with 7a.
Analogously, compounds 7b–l were synthesized by the appropriate
hydrazonoyl halides 1a–d and the appropriate 8a–c in boiling ethanol
containing triethylamine (Scheme 2). Acetophenone thiosemicarbazone

Pyrazolines and Thiadiazolines
1769
SCHEME 2
(10) was reacted 1a afforded 11a which reacted with benzaldehyde in
sodium hydroxide gave product identical in all respects (mp., mixed mp.
and spectra) with 7e.
On the other hand, benzene-1,2-dicarbaldehyde was reacted with
methyl hydrazinecarbodithioate gave {[2-2-aza-{2-[(methylthioxo-
methyl)amino]-vinyl}phenyl)-1-azavinyl]amino}methylthiomethane-1-
thione (12). Structure 12 was elucidated by elemental analysis,
spectra, and chemical transformation. Thus, 12 was reacted with
C-ethoxycarbonyl-N-phenylhydrazonoyl chloride in ethanolic tri-
ethyamine gave ethyl 2-[3-{2-[2,3-diaza-3-[5-ethoxycarbonyl)-3-phe-
nyl(1,3,4-thiadiazolin-2-ylidene)]prop-1-enyl]phenyl}-1,2-diazaprop-2-
FIGURE 1 X-Ray single crystal of [5-methyl-2-(3-phenyl-5-(2-thienyl)(2-
pyrazolinyl))(thiazol-4-yl)]phenyldiazene (7a).

1770
A. O. Abdelhamid and A. R. Sayed
enylidene]-3-phenyl-1,3,4-thiadiazoline-5-carboxylate (15) in a good
yield (Scheme 3). Structure 15 was confirmed by elemental anal-
ysis, spectra and alternative synthesis route. Thus, benzene-1,2-
dicarbaldehyde was reacted with 2,3-dihydro-1,3,4-thiadiazole 1617 in
ethanol afforded product identical in all respects (mp., mixed mp. and
spectra) with 15a.
FIGURE 2
The formation of thiadiazoline 15a can be explained via elimination
of methanethiol from cycloadduct 14a, which is assumed to be formed
via 1,3-dipolar cycloaddition of nitrile imide (generate in situ by treat-
ment of 1a with triethylamine) to C=S double bond of 12 or by its
stepwise path involving substitution via 1,3–addition of thiol 12 to ni-
trile imide to give a cyclic hydrazone 13a, which transformed to cyclic
intermediate 14a. Cyclization of the latter is achieved by elimination of
methanethiol to afford the final product 15. All attempts to isolate ei-
ther intermediate hydrazone 13a or cycloadduct 14a were unsuccessful
(c.f., Scheme 3).

Pyrazolines and Thiadiazolines
1771
Similar, compound 12 was reacted with the appropriate hydrazonoyl
halides 1b–h in ethanol containing triethylamine gave 2,3-dihydro-
1,3,4-thiadiazoles 15b–h, respectively.
Antimicrobial Activity
The tested microorganisms were gram +ve bacteria, gram -ve bacte-
ria, and some fungal plants. Sensitivity of the selected microorgan-
isms to some synthesized compounds were determined in vitro culture
that were dissolved in chloroform, the tests were carried out using
the filter paper and hole plate method.18,19 Studies on the biological
activity of compounds in comparison with Ampicillin and tetracy-
cline showed in Table I. In general all tested compounds were ca-
pable of a high inhibiting the growth of gram positive and gram
TABLE I Response of Various Microorganisms to Some Synthesized
Compounds in vitro (Culture)
Bacillus
Aspergills Candida
flvus albicans
Microorganisms/ Staphylococcus Streptococcus subtilis Echerichia
compound no.
albus(G+)
faecalis(G+)
(G+)
coli (G−) (Fungus) (fungus)
Ampicillin/
34R/27
37/31
33/30
39/34
0.0/0.0
20/37
tetracycline
7a
7b
7c
7d
7e
7f
7g
7h
7i
7k
7l
9
13
14
13
13
13
14
13
14
14
15
14
18
17
14
13
13
14
15
13
14
14
14
14
14
13
14
13
15
13
14
15
18
16
14
13
14
15
15
13
14
14
15
14
14
13
14
12
14
14
13
15
20
18
15
15
13
14
15
14
13
14
14
14
14
14
13
14
15
13
13
14
18
18
15
12
14
13
15
14
13
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
14
14
14
15
15
14
15
14
15
14
15
15
18
17
14
13
13
14
13
14
13
11
0.0
12
15a
15b
15c
15e
15f
15g
15h
0.0
0.0
0.0
0.0
0.0
0.0
St. Reference standard; Chloramphenicol was used as a standard antibacterial
agent; Terbinafin was used as a standard antifungal agent. Values show zone of
inhibition in mm. Diameter of the inhibition zones were: high (11–15 mm), moderate
(6–10 mm), slight (1–5 mm), and negative (0).

1772
A. O. Abdelhamid and A. R. Sayed
negative. Also, Table I showed the tested compounds were a high inhi-
bition towards Candida albicans (Fungus) and negative Aspergills flvus
(Fungus).
EXPERIMENTAL
All melting points were determined on an electrothermal appara-
tus and are uncorrected. IR spectra were recorded (KBr discs) on a
1
Shimadzu FT-IR 8201 PC spectrophotometer. H NMR spectra were
recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini 300
MHz spectrometer, and chemical shifts are expressed in δ units us-
ing TMS as an internal reference. Mass spectra were recorded on a
GC-MS QP 1000 EX Shimadzu. Elemental analyses were carried out
at the Microanalytical Canter of the Cairo University. X-ray single
crystals analysis was obtained from the National Research Centre,
Dokki, Cairo, Egypt. Hydrazonoyl halides were prepared as previously
reported.20−25
Synthesis of [5-Substituted-2-(3-phenyl-5-(2-substituted)(2-
pyrazolinyl))(thiazol-4-yl)]phenyldiazene (7a–l),
General Method
Equimolar amounts of the appropriate hydrazonoyl halides 1a–d (5
mmol), thiosemicarbazide (0.46 g, 5 mmol), the appropriate of 1-phenyl-
3-(2-substituted)prop-2-ene-1-one (3a–c), and triethylamine (0.75 mL,
5 mmol) in ethanol (20 mL) were heated under reflux for 3 h. The re-
sulting solid was collected and recrystallized from acetic acid to give
7a–l (Tables II and III).
Synthesis of [5-Methyl-2-(3-phenyl-
5-(2-thienyl)(2-pyrazolinyl))(thiazol-4-yl)]phenyldiazene (7a)
Method A.
A
mixture of amino(3-phenyl-5-(2-thienyl)(2-
pyrazolinyl))methane-1-thione (8a) (1.40 g, 5 mmol), C-acetyl-N-
phenylhdrazonoyl chloride 1a (0.98 g, 5 mmol), and triethylamine
(0.75 mL, 5 mmol) in ethanol (20 mL) was boiled under reflux for 2 h.
The resulting solid was collected and recrystallized from acetic acid to
give 7a (Tables II and III).
Method B.
A mixture of (2-hydrazino-4-methyl)(1,3-thiazol-5-
yl))phenyldiazene (9a, 1.16 g, 5 mmol) and 1-phenyl-3-(2-thienyl)prop-
2-ene-1-one (3a) (1.16 g, 5 mmol)) in ethanol (20 mL) was boiled under
reflux for 2 h. The result solid was collected and recrystallized to give
identical product with7a.

1773

1774

Pyrazolines and Thiadiazolines
1775
Synthesis of [5-Methyl-2-(3-phenyl-
5-(2-phenyl)(2-pyrazolinyl))(thiazol-4-yl)]phenyldiazene (7e)
Equimolar amounts of (1-aza-2-phenylprop-1-enyl)[4-methyl-5-
(phenyldiazenyl)(1,3-thiazol-2-yl)]amine (11) (1.60 g, 5 mmol) and ben-
zaldehyde (0.53 g, 5 mmol) in ethanol (20 mL) was cooled at 5◦C then
added sodium hydroxide solution (4N, 10 mL) portion wise while stir-
ring. The resulting solid was collected and recrystallized from acetic
acid to give 7e.
Synthesis of Amino(3-Phenyl-5-substituted
(2-pyrazolinyl))methane-1-thione (8a–c)
A mixture of the appropriate 3a–c (5 mmol) and thiosemicarbazide
(0.46 g, 5 mmol) in ethanol (20 mL) was heated under refluxed for 3
h. The resulting solid was collected and recrystallized from ethanol to
give 8a–c, respectively (Tables II and III).
Synthesis of
(2-Hydrazino-4-methyl)(1,3-thiazol-5-yl))phenyldiazene (9a)
A mixture of C-acetyl-N-phenylhdrazonoyl chloride 1a (0.98 g, 5
mmol), thisemicarbazide (0.5 g, 5 mmol), and triethylamine (0.75 mL, 5
mmol) in ethanol (20 mL) was boiled under reflux for 2 h. The resulting
solid was collected and recrystallized from ethanol to give 9a (Tables II
and III).
Synthesis of (1-Aza-2-phenylprop-1-
enyl)[4-methyl-5-(phenyldiazenyl)(1,3-thiazol-2-yl)]amine (11)
A mixture of C-acetyl-N-phenylhdrazonoyl chloride (1a) (0.98 g, 5
mmol) and [(-1-aza-2-phenylprop-1-enyl)amino]aminometane-1-thione
(10) (0.96 g, 5 mmol) and triethylamine (0.75 mL, 5 mmol) in ethanol (20
mL) was heated under reflux for 2 h. The resulting solid was collected
and recrystallized to give 11 (Tables II and III).
Synthesis of[2-2-Aza-2-[(methylthioxomethyl)amino]-
vinylphenyl)-1-azavinyl]-aminomethylthiomethane-1-thione
(12)
Equimolar amount of benzene-1,2-dicarbaldehyde (0.67 g, 5 mmol)
and methyl hydrazinecarbodithioate (0.66 g, 5 mmol) in 2-propanol (40
mL) was refluxed for 30 min. The reaction mixture was cooled and solid
formed was collected and recrystallized from ethanol to give 12 (Tables
I and II).

1776
A. O. Abdelhamid and A. R. Sayed
Synthesis of Ethyl 2-[3-2-[2,3-Diaza-3-[3,5-disubstituted
(1,3,4-Thiadiazolin-2-ylidene)]prop-1-enyl]phenyl-1,2-
diazaprop-2-enylidene]-3,5-disubstituted 1,3,4-thiadiazoline
15a–h
Equimolar amount of the appropriate of hydrazonoyl halides (5
mmol) and {[2-2-aza-2-[(methylthioxomethyl)amino]-vinyl}phenyl)-1-
azavinyl]aminomethylthio-methane-1-thione (12) (1.7 g, 5 mmol) in
ethanol (40 ml) was stirred for 2 h. The resulting solid was collected
and recrystallized from dioxan to give 15a–h, respectively (Tables II
and III).
X-Ray Structural Analysis of Compound 7a
Crystal data C23H19N5S2, M = 429.57, triclinic. PT, a = 10.4778 (4)A◦,
b = 10.6635 (4)A◦, c = 11.0283 (6)A◦, α = 63.852 (2)◦, β = 86.687 (2)◦,
γ = 74.257 (2)◦, V = 1061.87 (8)3A, Z = 2.
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