A new type of synthesis of 1,2,3- Thiadiazole and 1,2,3-diazaphosphole derivatives via-hurd-mori cyclization

Article abstract of DOI:10.1155/2012/457949

We present a short and efficient synthesis of the title compounds starting with cheap and readily available camphor and derivatives of acetophenone. The optimized sequence allows the large-scale preparation of this new type of synthesis in a few steps. Ne

Full text of DOI:10.1155/2012/457949

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(3), 1276-1287
A New Type of Synthesis of 1,2,3- Thiadiazole and
1,2,3-Diazaphosphole Derivatives Via-Hurd-Mori
Cyclization
MONA A. HOSNY*, TAGHREED H. EL-SAYED, EMTITHAL A. EL-SAWI
Department of Chemistry, Faculty of Women for Arts, Science and Education, Ain
Shams University, Cairo, Egypt.
monaaminhosny@yahoo.com
Received 13 November 2011; Accepted 15 January 2012
Abstract: We present a short and efficient synthesis of the title compounds
starting with cheap and readily available camphor and derivatives of
acetophenone. The optimized sequence allows the large-scale preparation of this
new type of synthesis in a few steps. New 1, 2,3-thiadiazole and 1,2,3-
diazaphosphole derivatives 11-20, were prepared from the ketones 1-5 via the
corresponding semicarbazones 6-10. The Hurd-Mori and Lalezari methods
were used, respectively, for the preparation of these 1,2,3-thiadiazole and
1,2,3-diazaphosphole derivatives. These derivatives exhibit anticancer effect
due to their high potential biological activity.
Keywords: Semicarbazone, 1,2,3-diazaphosphole, 1,2,3-thiadiazole.
Introduction
Derivatives of 1,2,3-thiadiazoles and 1,2,3-diazaphosphole are known to exhibit anti-
inflammatory1-3, antiviral4,5, analgesic 6,7, antimicrobial8-12, anticonvulsant13-16 and
antidepressant activity.17 Among the pharmacological profiles of 1,2,3-thiadiazoles and
1,2,3-diazaphospholes, their antimicrobial, anticonvulsant and antidepressant properties
seem to be the best documented. 1,2,3-thiadiazoles and related compounds are of great
interest in chemistry owing to their bioactivity of certain plant growth regulating effect
as well as antimicrobial activity.18,19 In spite of the obvious attraction of P and S-
heterocycles, only a few preparative routes have been described. Antitubercular
activities of thiadiazoles linked with aromatic cycles through the methyleneoxy group
have also been reported and compounds of this type have shown inhibition on both
cycloxygenase and 5-lipoxygenase activities.2,20 Lee and coworkers have synthesized
some thiadiazoles with antihelminthic activities.21 More recently, sulfonamide
derivatives of 1,3,4-thiadiazoles have been reported to behave as a modulator of
anticancer therapies in combination with some cytotoxic compounds.22-25 Lalezari et

A New Type of Synthesis of 1,2,3- Thiadiazole and 1,2,3-Diazaphosphole
7711
al.26-28 were the first to report the synthesis of 1,2,3-thiadiazole system, which had been
prepared previously by Hurd and Mori.29 We report herein the synthesis of new
compounds containing 1,2,3-thiadiazole and 1,2,3-diazaphosphole ring30,31 using the
Lalezari et al. and Hurd and Mori methods. Some diazaphospholes demonstrated
insecticidal, bactericidal, antiviral, antitumor and anticarcinogenic activity.32 As a part
of our ongoing programme, aimed at searching for novel antibacterial and antiviral
agents with high activity and low toxicity, a synthetic route has been developed to the
title compounds.
Experimental Section
Melting points were taken on Gallen Kamp melting apparatus and were uncorrected.
Thin layer chromatography was performed with fluorescent silica gel plates HF254
(Merck), and plates were viewed under UV254 and 265 light. Infrared spectra (-cm-1)
were recorded on Bruker Vector Germany and on Mattson FT-IR 1000, using KBr
1
disks. Mass spectra are measured on GCQ Finnigan MAT. H-NMR spectra were
recorded on Gemini-200 MHZ NMR spectrometer in DMSO-d6 spectra were internally
referenced to TMS. Peaks are reported in ppm. Downfield of TMS. The antibacterial
activity were determined in microanalytical center Cairo University and anticancer
activity was done in National Cancer Institute, Cancer Biology Department,
Pharmacology, Cairo University. D-(+)-camphor, di-methoxy acetophenone p-bromo
acetophenone, p-nitro acetophenone p-amino acetophenone were obtained from Fluka
or Aldrich.
General Procedure for the Preparation of Thiosemicarbazones (6,7,8,9,10)
A mixture of Camphor (1, 0.95 equivalent) or 3,4- dimethoxy acetophenone (2, 0.95
equivalent) or P-bromoacetophenone (3, 0.95 equivalent) or p-nitro acetophenone (4,
0.95 equivalent) or p-amino acetophenone (5, 0.95 equivalent), respectively and
thiosemicarbazide (1.00 equivalent) was dissolved in absolute ethanol (30 ml). The
mixture was heated for 5 hr. under reflux, then the solvent was removed under vacuum
and the residue was washed with diethyl ether. A recrystallization from ethyl alcohol
was carried out.
General Procedure for the Preparation of 1,2,3-thiadiazole (11,12,13,14,15)
An excess amount of thionyl chloride was stirred at room temperature and the
thiosemicarbazones 6 or 7 or 8 or 9 or 10 were added in several portions. The mixtures
were stirred at r.t. overnight until no more hydrogen chloride was produced, the product
was washed with diethyl ether to give a good yields of the corresponding 1, 2, 3-
thiodiazoles as fine powders. A recrystallization from ethyl alcohol was carried out.
General procedure for the preparation of 1,2,3-diazaphosphole compounds
(16,17,18,19,20)
Each of thiosemicarbazones 6 or 7 or 8 or 9 or 10 (1 mol) and triphenyl phosphine (1
mol) were dissolved in tetrahydrofuran(10 ml) and the mixture was stirred at room
temperature for 2 days. The product was washed with diethyl ether to give a good
yields of the corresponding 1,2,3-diazaphospholes as five powders. A recrystallization
from ethyl alcohol was carried out.

7711 Mona A. Hosny
Results and Discussion
In the present study, new 1,2,3-thiadiazole and 1,2,3-diazaphosphole derivatives were
obtained started from a variety of ketones (1-5) containing -methylene group (scheme
1) that were first converted into their corresponding semicarbazones and then further
converted into 1,2,3-thiadiazole by reaction of thiosemicarbazide with thionyl
chloride33-37 and into 1,2,3-diazaphosphole ring derivatives by triphenyl phosphine
reductive ring closure of these thiosemicarbazide derivatives.30-32
H3C
O
CH3
H3C
O
H3C
H3C
O
H3C
O
C
C
C
C
H
3CO
CH3
(1)
OCH3
(2)
NH2
Br
NO2
O
(3)
(5)
(4)
Scheme (1): Ketones used in the preparation of new 1,2,3-thiadiazole and 1,2,3-
diazaphosphole compounds
The general equations for the preparation of 1,2,3-thiadiazole and 1,2,3-
diazaphosphole derivatives are shown in scheme 2.
X
NH
O
N
H2N
X
N
H
R CH3
R CH3
SOCl2
TPP
S
C
Hurd and Mori Method
X=
NH
2
X
Ph
N P Ph
Ph
N
N
R
S
HN
R
1,2,3-thiadiazole
ring
1,2,3-diazaphosphole
ring
Scheme (2)

A New Type of Synthesis of 1,2,3- Thiadiazole and 1,2,3-Diazaphosphole
7711
Table (1) shows the structures of the newly prepared compounds, melting point
ranges and the percentage yields of these compounds.
Number
Structure
Melting Point (oC)
%Yield
CH3
H3C
6
178-180
96%
CH3
N-NH
C
S
NH2
S
HN
N
NH2
H3C
C
7
222
95%
H3CO
OCH3
S
HN
NH2
H3C
N
C
8
140
94%
Br
S
HN
N
NH2
H3C
C
9
262
97%
NO2
HN
S
NH2
H3C
N
C
10
140
95%
NH2

7711 Mona A. Hosny
Number
Structure
Melting Point (oC)
%Yield
CH3
H3C
S
11
Decompose at 266
60%
N
S
CH3
N
NH2.HCl
S
C
N
S
H2N
N
12
13
14
116
Decompose at 240
190
72%
65%
63%
H3CO
OCH3
NHSOCl
N
N
Br
NHSOCl
N
N
NO2
S
C
H2N
N
S
N
15
Above 300
69%
NH2

A New Type of Synthesis of 1,2,3- Thiadiazole and 1,2,3-Diazaphosphole
7717
Number
16
Structure
CH3
Melting Point (oC)
%Yield
H3C
Ph
Ph
Ph
P
80
64%
N
CH3
S
N
H
NH2
S
Ph
Ph
Ph
C
H2N
N
P
N
17
210
65%
H3CO
H
OC
3
S
Ph
Ph
Ph
C
H2N
N
P
N
18
19
20
180
250
125
69%
66%
70%
Br
S
Ph
Ph
Ph
C
H2N
N
P
N
NO2
S
Ph
Ph
Ph
C
H2N
N
P
N
NH2

7717 Mona A. Hosny
Compound (14) was of particular interest as it represents the unexpected
compound in contrast the previous structures. Scheme 3 shows the proposed
mechanism for the formation of compound (14). Its structure was confirmed by I.R, 1H-
NMR, mass spectrometry.
NHSOCl
N
S
N
NH2
N N
H
SOCl2
O2N
Stirring
Overnight
CH3
(14)
NO2
Scheme (3): Mechanism for the formation of compound (14).
Characterization data of newly compounds hydrazones (6-10) and 1,2,3-
thiadiazole (11-15) and 1,2,3-diazaphosphole (16-20).
Compound (6): White solid, IR (KBr) (cm-1): :3369- 3264 (NH2), 3178 (NH), 2966
1
(CH3, str.), 1643 (C=N), 1282 (C=S); MS (m/z %): 225 (53, 43%), 74 (100%); HNMR,
(DMSO-d6) : 0.7-0.95 (3CH3), 1.24 (CH2), 1.98 (CH2), 1.94 (CH2), 1.75
(CH), 2.07 (NH2), 7.1 (NH).
Compound (7): White solid, I.R (KBr) (cm-1): : 3374-3266- (NH2), 3155 (NH), 1640
1
(C=N), 1250 (C=S); MS (m/z %): 253 (100%); H-NMR, (DMSO-d6) : 3.78-3.82 (2
OCH3), 1.18 (SH), 2.52 (NH2 tauto.), 2.27 (CH3), 6.91-8.22 (Ar. protons), 9.75 (NH).
Compound (8): Brown solid, I.R. (KBr) (cm-1): : 3446-3330 (NH2), 3154 (NH),
1671 (C=N), 1268 (C=S); MS (m/z %): 272 (8.91%), 256 (100%); 1H-NMR, (DMSOd6).
: 1.21 (SH), 8.29 (NH2 tauto.), 2.27 (CH3), 6.86-7.98 (Ar. protons), 10.24 (NH).
Compound (9): Yellow solid, IR (KBr) (cm-1): :3478-3355 (NH2), 3197 (NH), 1585.
(C=N), 1247 (C=S); MS (m/z %): 238 (14.34%), 223 (100%); 1H-NMR, (DMSO-d6).
: 1.05 (SH), 2.35 (CH3), 7.48-8.20 (Ar. Protons), 8.45 (NH2), 10.36 (NH).
Compound (10): Brown solid, IR (KBr) (cm-1): :3392 - 3249 (NH2), 3154 (NH),
1
1660 (C=N), 1284 (C=S); MS (m/z %): 208 (24.60%), 59 (100%); H-NMR, (DMSOd6).
: 2.38 (NH2), 2.26 (CH3), 6.62-7.93 (Ar. protons), 8.23 (Ar. NH2), 10.18 (Ar.
protons).
Compound (11): Pale orange, I.R (KBr) (cm-1): : 3046-3138 (NH3+), 1618 (C=N),
1
1268 (C=S), 1402 (C-S); MS (m/z%): 293 (1.44%), 64 (100%); H-NMR, (DMSO-d6).
: 1.23 (CH), 1.05 (SH), 4.13 (NH), 7.5
3-7.23 (Ar. protons).

A New Type of Synthesis of 1,2,3- Thiadiazole and 1,2,3-Diazaphosphole
7711
Compound (12): Yellow solid, IR (KBr) (cm-1): : 3390 -3129 (NH2), 1591 (C=C),
1404 (C-S), 1268 (C=S); MS (m/z %): 283 (22.80%), 165 (100%); 1H-NMR,
(DMSO-d6) : 1.3 (CH3), 3.8 (2OCH3), 4.64 (NH2), 7.12-7.62 (Ar. protons).
Compound (13): Brown solid, IR (KBr) (cm-1): : 3135 (NH), 2815(CH2 aliphatic),1683
1
(C=N),; MS (m/z%): 323 (23.80%), 64 (100%); H-NMR, (DMSO-d6) : 4.62.
(NH), 5.48 (CH), 11.64 (NH), 7.19-7.7 (Ar. protons).
Compound (14): Bage solid, IR (KBr) (cm-1): : 3165 (NH), 3040 (Ar. C-H), 2840 (CH2
aliphatic),1590 (C=N), MS (m/z%): 287 (10.4%), 60 (100%); 1H-NMR, (DMSOd6).
: 2.35 (CH2) 83.89 (NH), 8.02-8.44 (Ar. protons).
Compound (15): Yellow solid, IR (KBr) (cm-1): :3480- 3320 (NH2), ,3129 NH,3041 (Ar.
C-H),. 2805 (CH2 – aliphatic), 1627 (C=N), 1600 (Ar-C=C), 1226 (C=S); MS.
(m/z %): 238 (19.97%), 64 (100%); 1H-NMR, (DMSO-d6) 1.13 (CH2), 4.52 (NH2),
6.73 (NH2-Ar), 7.1-7.61 (Ar. protons).
Compound (16): White solid, IR (KBr) (cm-1): : 3450 -3399 (NH2), 3064 (NH),
1654 (C=C), 1473 (-P-Ph), 1268 (C=S), 1089 (C-P ); MS (m/z %): 485 (0.03%),
1
183 (100%); H-NMR, (DMSO-d6) : 1.06 (3CH3), 4.36 (NH2), 7.25-7.48 (Ar.
protons), 7.58 (NH).
Compound (17): Pale Bage solid, IR (KBr) (cm-1): :3372-3264 (NH2), 2992-2840 (CH2 –
Aliphatic), 1641 (C=N), 1604 (Ar. C=C), 1438 (PPh),1253 (C=S), 1081 (C-P ), MS (m/z%)
482 (0.06%), 277 (100%); 1H-NMR, (DMSO-d6) : 1.8(CH), 2.27 (NH2), 3.78, 3.82
(2OCH3), 6.91-8.22 (Ar. protons),
10.07 (NH).
Compound (18): Brown solid, IR (KBr) (cm-1): : 3434-3360 (NH2), 3035 (CH-Ar.),
2880 (CH2 – aliphatic), 1600 (ArC=C), 1577 (C=N), 1481 (P-Ph), 1286 (C=S),1083.
(C–P); MS (m/z %): 532 (3.98%), 60 (100%); 1H-NMR, (DMSO-d6): 2.27 (CH), 6.82-
7.88 (Ar. protons), 8.2 (NH-C-SH).
Compound (19): Orange solid, IR (KBr) (cm-1): : 3477-3354 (NH2), 3070 (Ar. C-H),
2968 (CH2 aliphatic). 1680 (C=N), 1443 (P-Ph), 1247 (C=S),
1078 (C–P); MS (m/z %): 498 (0.33%), 60 (100%); 1H-NMR, (DMSO-d6) :
1.75 (SH), 2.35 (NH), 2.36 (NH), 4.48 (CH-ethylene), 7.25-8.45 (Ar-protons).
Compound (20): Pale Bage solid, IR (KBr) (cm-1): : 3390-3320 (NH2), 3041 (ArC-H),
2950 (CH2 aliphatic), 1595 (C=N), 1480 (P-Ph), 1267 (C=S), 1116 (C- P ), ,
MS (m/z %): 468 (1.41%), 277 (100%); 1H-NMR (DMSO-d6) : 1.14 (SH), 2.22(NH), 2.38
(NH), 4.47 (CH–ethylene), 6.83-8.16 (Ar. protons).
Biological Activity
Standard discs of Tetracycline (Antibacterial agent), amphotericin B (Antifungal agent)
served as positive controls for antimicrobial activity but filter discs impregnated with
10 µl of solvent (distilled water, chloroform, DMSO) were used as a negative control.

7711 Mona A. Hosny
The agar used is Meuller-Hinton agar that is rigorously tested for composition and
pH. Further the depth of the agar in the plate is a factor to be considered in the disc diffusion
method. This method is well documented and standard zones of inhibition have been
determined for susceptible and resistant values.
Blank paper disks (Schleicher and Schuell, Spain) with a diameter of 8.0 mm were
impregnated 10 µ 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 a "Zone of inhibition" or
"clear zone".
Table (2): Antifungal activity data and antibacterial activity.
Inhibition Zone Diameter (mm/mg sample)
Compound No.
Af
Ca
Ec
Sa
Tetracycline
antibacterial
agent
–
–
33
32
Amphotericin B
antifungal agent
18
20
–
–
6
7
8
9
13
0.0
33 (US)
0.0
13
0.0
11
0.0
0.0
12
16
10
12
10
12
13
14
13
10
14
13
10
14
12
18
14
10
11
10
11
13
13
14
11
15
12
10
13
12
20
10
11
12
13
14
15
16
17
18
19
20
0.0
12
12
13
0.0
0.0
14
0.0
36 (US)
0.0
12
11
0.0
0.0
13
0.0
11
11
0.0
10
AF-Aspergillus flavus, Ca–Candida albicans, Ec- Escherichia coli, Sa – Staphylococcus
aureus
US: Unsporulated area.

A New Type of Synthesis of 1,2,3- Thiadiazole and 1,2,3-Diazaphosphole
7711
Antitumor Screening
Chemotherapy is a major therapeutic approach for the treatment of both localized
and metastasized cancers. In the present work newly compounds 1,2,3-thiadiazole and 1,2,3-
diazaphosphole were evaluated as inhibitors of the growth of breast cancer cell line in
comparison to the known anticancer drug: Doxorubicin as a trial to get more effective and
less toxic agent.
Preliminary experiments were done using the human tumor cell line to identify the
potential toxicity of four chosen selected newly synthesized compounds (11,12,16,17) (Fig.
1) in comparison to the known anticancer drug: doxorubicin by SRB using the method
Skehan et al.38



Cells were plated in 96-multiwell plate (104 cells/well) for 24 hrs before treatment
with compounds to allow attachment of cell to the wall of the plate.
Different concentration of the compound under test (0, 1, 2.5, 5 and 10g/ml) were
added to the cell monolayer triplicate wells prepared for each individual dose.
Monolayer cells were incubated with the compounds for 48 hrs at 37oC and
atmosphere of 5% CO2.


After 48 hrs, cells were fixed, washed and stained with sulfo-rhodamine -  stain.
Excess stain was washed with acetic acid and attached stain was recovered with tris
EDTA buffer.


Color intensity was measured in an ELISA reader.
The relation between surviving fraction and drug concentration is plotted to get the
survival curve of each tumor cell line after the specified compound.
MCF7-DOX
MCF7-11
MCF7-16
MCF7-12
MCF7-17
1.2
1
0.8
0.6
0.4
0.2
0
0
10
20
30
40
50
60
CONC: ug/mL
Figure (1): Drug cytotoxicity of product 11,16,12,17 compared to doxorubicin.

7711 Mona A. Hosny
Table (3): Effect of some selected newly synthesized compounds on breast cancer cell line.
Compound
IC50
Doxorubicin
3.13 g/ml
12.8 g/ml
5.4 g/ml
8.1 g/ml
6.79 g/ml
11
16
12
17
IC50: Dose of the compound which reduces survival to 50%.
Conclusion
In connection with our work on derivatives of acetophenone herein we describe a new
type procedure for the synthesis of 1,2,3-thiadiazole and 1,2,3-diazaphosphole
compounds via-Hurd Mori cyclization. The Hurd-Mori reaction is by far the most
widely used method in the research on 1,2,3-thiadiazoles, and some reactions are
carried out on an industrial scale. In view of these facts, the aim of the present study
was to obtain 1,2,3-thiadiazole and 1,2,3-diazaphosphole derivatives where synthesized
as antitumor agents. The antitumor activity results indicated that all the four derivatives
showed antitumor activity against the tested breast cancer cell line but with varying
intensities in comparison to the known anticancer drug: doxorubicin.
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