Synthesis of biologically active phenoxy derivatives of substituted benzothiazole organophosphates

Article abstract of DOI:10.1002/hc.20582

The reaction of S-(phenyl benzothiazolyl-2)phosphorodichloridothioate/ phosphorodichloridodithioatewith 2mol of phenol/4-chlorophenol/4-nitrophenol in the presence of stoichiometric amounts of triethylamine in dry THF/CH ₂Cl₂ has afforded a series of the corresponding organophosphate phenoxy derivatives (1a, 1b, 2a, 2b, and 3a, 3b). Plausible structures have been proposed on the basis of elemental analysis, IR, ¹H NMR, ³¹P NMR, and mass spectral studies. The antibacterial activity of these organophosphate phenoxy derivatives has been evaluated against pathogenic bacteria Staphylococcus aureus (+ve) and Escherichia coli (-ve). The antifungal activity of these organophosphate phenoxy derivatives has been evaluated against pathogenic fungi Aspergillus niger and Fusarium oxysporium. The results indicate that organophosphate phenoxy derivatives are found more active than the parent compounds.

Full text of DOI:10.1002/hc.20582

Heteroatom Chemistry
Volume 21, Number 2, 2010
Synthesis of Biologically Active Phenoxy
Derivatives of Substituted Benzothiazole
Organophosphates
Priyanka Jhajharia, Mahesh Kumar Samota, and Gita Seth
Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
Received 3 November 2008
which have valuable antifungal, antitumor, biolog-
ABSTRACT: The reaction of S-(phenyl benzothi-
azolyl-2)phosphorodichloridothioate/phosphorodich-
loridodithioate with 2 mol of phenol/4-chlorophenol/4-
nitrophenol in the presence of stoichiometric amounts
of triethylamine in dry THF/CH2Cl2 has afforded a se-
ries of the corresponding organophosphate phenoxy
derivatives (1a, 1b, 2a, 2b, and 3a, 3b). Plausible
structures have been proposed on the basis of elemen-
tal analysis, IR, 1H NMR, 31P NMR, and mass spectral
studies. The antibacterial activity of these organophos-
phate phenoxy derivatives has been evaluated against
pathogenic bacteria Staphylococcus aureus (+ve)
and Escherichia coli (−ve). The antifungal activ-
ity of these organophosphate phenoxy derivatives has
been evaluated against pathogenic fungi Aspergillus
niger and Fusarium oxysporium. The results indi-
cate that organophosphate phenoxy derivatives are
found more active than the parent compounds.
ical, and pharmacological activities, were investi-
gated [2–7]. Some of the substituted benzothiazoles
and their chelate metal complexes are being used as
white organic light-emitting devices [8].
Organophosphorus compounds containing het-
erocyclic moiety increase the protonation at the site
of pesticides and enhance their biological activity
[9]. Organophosphates exert their biological action
on insects and mammals by attacking the neural
transmission system and inhibiting the function of
acetylcholinesterase enzyme [10]. Various phospho-
rylated compounds of benzothiazole and amines are
also associated with antifungal activities [11,12].
The reaction of phenols with phosphonates or thio-
phosphonates enhanced their biocidal activity [13].
In continuation of our work on organophosphates
[14,15], we report here the synthesis of biologically
active phenoxy derivatives of substituted benzothia-
zole organophosphates.
ꢀ
C
2010 Wiley Periodicals, Inc. Heteroatom Chem 21:84–
88, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20582
RESULTS AND DISCUSSION
The reaction of S-(phenyl benzothiazolyl-2)
phosphorodichloridothioate/phosphorodichlorido-
dithioate with 2 mol of phenol/4-chlorophenol/4-
nitrophenol in the presence of stoichiometric
amounts of triethylamine in dry THF/CH2Cl2 has
afforded a series of the corresponding organophos-
phate phenoxy derivatives (1a, 1b, 2a, 2b, 3a, and
3b). A schematic presentation of these reactions is
given in Fig. 1, and physical properties, synthetic
and analytical data of organophosphate phenoxy
derivatives are given in Table 1. All these reactions
are quite facile and completed in 10–12 h after
INTRODUCTION
Compounds containing the thiazole nucleus have
proven to be efficacious as antifungal agent, and
many of them have gained wide acceptance in clin-
ical practice [1]. Benzothiazoles are a part of the
molecular structure of a large number of natural
products. In recent time, benzothiazole derivatives,
Correspondence
to:
Priyanka
Jhajharia;
e-mail:
priyankajhajharia@yahoo.com.
c
ꢀ
2010 Wiley Periodicals, Inc.
84

Synthesis of Biologically Active Phenoxy Derivatives of Substituted Benzothiazole Organophosphates 85
TABLE 1 Physical Properties, Synthetic, and Analytical Data of Organophosphate Phenoxy Derivatives (1a, 1b, 2a, 2b, 3a,
and 3b)
Analysis% Found (Calcd.)
S. No.
1.
Compound
m p (◦C)
198–200
200–204
195–198
172–178
184–188
167–171
Yield (%)
C
H
N
P
S
M. Wt. Found (Calcd.)
1a
1b
2a
2b
3a
3b
42
50
44
48
45
38
63.01
(63.15)
59.68
(61.08)
56.11
(56.28)
54.53
(54.64)
58.49
3.74
(3.82)
3.59
(3.70)
2.68
(3.02)
2.84
(2.93)
3.07
2.88
(2.94)
2.74
(2.84)
7.69
(7.88)
7.57
(7.64)
2.58
6.37
(6.51)
6.09
(6.30)
5.72
(5.80)
5.54
(5.64)
5.93
13.32
(13.48)
12.89
(13.04)
14.86
(14.99)
17.42
(17.50)
12.23
473.08
(475.52)
489.36
(491.58)
532.01
(533.50)
548.42
(549.57)
510.03
2.
3.
4.
5.
(58.60)
56.68
(3.15)
2.97
(2.73)
2.52
(6.04)
5.76
(12.51)
17.99
(512.40)
526.88
6.
(56.82)
(3.05)
(2.65)
(5.86)
(18.20)
(528.47)
TABLE
2 ) of
Assignment of Main IR Bands (cm−1
Organophosphate Phenoxy Derivatives (1a, 1b, 2a, 2b, 3a,
3b)
S. No. Compound ν(P O C) ν(P O) ν(P S) ν(NO2)
1.
2.
1a
1b
1164–935
1130–950
1205
790 (I)
630 (II)
3.
4.
2a
2b
1160–935
1155–974
1190
1335
1530
1332
788 (I)
630 (II) 1225
5.
6.
3a
3b
1184–940
1135–965
1182
775 (I)
612 (II)
refluxing. The resulted compounds are hygroscopic
and are soluble in dimethylsulfoxide.
IR Spectra
The assignments of some important bands are
summarized in Table 2. The absorption band at
500–590 cm−1, owing to νP Cl of S-(phenyl benzo-
thiazolyl-2)phosphorodichloridothioate/phosphoro-
dichloridodithioate, disappeared in the spectra of
organophosphate phenoxy derivatives (1a, 1b, 2a,
2b, 3a, and 3b). New bands appeared in the region
935–1184 cm−1 due to νP O C (aryl). The νP O
band is observed at 1182–1205 cm−1. The νP S (I)
and νP S (II) bands are observed at 775–790 cm−1
and 612–650 cm−1, respectively [16].
1H NMR and 31P NMR Spectra
1
The characteristic signals in H NMR and 31P NMR
FIGURE 1 Schematic presentation of organophosphate
phenoxy derivatives.
spectra of organophosphate phenoxy derivatives (1a,
1b, 2a, 2b, 3a, 3b) are summarized in Table 3. All
Heteroatom Chemistry DOI 10.1002/hc

86 Jhajharia, Samota, and Seth
TABLE
3
1H NMR and 31P NMR spectral Data of
TABLE 4 Mass Spectral Data of 2a
organophosphate Phenoxy Derivatives (1a, 1b, 2a, 2b, 3a,
3b)
Compound
m/z (%)
2a
562 (12.34%), 422.9 (13.12%), 278 (14%)
240 (10.52), 208.12 (16.4%) 131.21 (25.3%)
S. No. Compounds
1H NMR
31P NMR
1.
2.
3.
4.
5.
6.
1a
1b
2a
2b
3a
3b
7.0–7.4 (m, 18H, Ar-H)
7.1–7.4 (m, 18H, Ar-H)
7.2–7.6 (m, 16H, Ar-H)
7.2–7.5 (m, 16H, Ar-H)
7.4–7.8 (m, 16H, Ar-H)
7.4–8.2 (m, 16H, Ar-H)
64.3
69.2
59.0
63.4
62.1
66.4
at m/z 131.21. The intensity of all the peaks is very
weak. Relative abundance of the ions is represented
in Table 4.
ANTIBACTERIAL ACTIVITY
the organophosphate phenoxy derivatives show mul-
tiplets in the region of δ 7.0–8.2 ppm attributable to
the aromatic protons of a phenyl ring along with 2-
The results of the antibacterial activity of
organophosphate phenoxy derivatives (1a, 1b, 2a,
2b, 3a, 3b) have been compared with standard strep-
tomycin. The organisms selected for the studies are
Staphylococcus aureus (+ve) and Escherichia coli
(−ve). The antibacterial activity was evaluated by a
paper disk plate method. The results of antibacterial
screening of 1a, 1b, 2a, 2b, 3a, and 3b showed that
4-chlorophenol derivatives show the highest bacte-
ricidal activity among all the derivatives, but they
show less activity than standard streptomycin. All
the results are summarized in Table 5.
substituted phenyl and a benzothiazolyl ring. The 31
P
NMR spectra of organophosphate phenoxy deriva-
tives (1a, 1b, 2a, 2b, 3a, 3b) have been observed at
somewhat downfield at δ 59.0–69.2 ppm [17].
Mass Spectra
The splitting pattern of the mass spectrum of 2a is
represented in Fig. 2. The molecular ion peak ap-
pears at m/z 562, confirming the formation of 2a.
This peak after removal of two p-nitrophenoxy rad-
icals in the subsequent steps generates the ions at
m/z 422.9 and 278, respectively. Further fragmenta-
tion involves removal of the radical PO, and a peak
appears at m/z 240. It may further lose the sulfur
radical, and a peak appears m/z 208.12. This peak
after removal of a phenyl moiety produces an ion
ANTIFUNGAL ACTIVITY
The results of antifungal activity of organophosphate
phenoxy derivatives (1a, 1b, 2a, 2b, 3a, 3b) are sum-
marized in Table 6. The organophosphate phenoxy
derivatives have been screened for fungicidal prop-
erties against Aspergillus niger and Fusarium oxys-
porium at concentrations of 50 and 200 ppm. The
radial growth method was used to check an activity
against fungi by taking Dithane M-45 as a standard.
The inference drawn from the table revealed that the
activity of organophosphate phenoxy derivatives in-
creases with the increase in the concentration and
derivatives having P S bonds are more toxic than
derivatives having P O bonds. The toxicity of all
these organophosphate phenoxy derivatives is quite
high, but it is less than the standard Dithane M-45.
EXPERIMENTAL
All commercial reagents and solvents were dried and
distilled by common methods before use. Phospho-
rus oxychloride/phosphorus thiochloride were pur-
chased from Fluka. Melting points were determined
by the capillary method and are uncorrected. All op-
erations were carried out in dry equipment under
1
nitrogen atmosphere. H NMR data were recorded
FIGURE 2 Splitting pattern of the mass spectrum of 2a.
on JEOL FX 90Q/JEOL AL 300 MHz FT NMR
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Biologically Active Phenoxy Derivatives of Substituted Benzothiazole Organophosphates 87
TABLE 5 Antibacterial Screening Data of Organophosphate Phenoxy Derivatives (1a-1b, 2a-2b & 3a-3b)
Diameter of Inhibition Zone (mm) after 24 h (Concentration in ppm)
Staphylococcus aureus (+ve)
Escherichia coli (−ve)
S. No.
Compound
250
500
250
500
1.
2.
3.
4.
5.
6.
1a
1b
2a
2b
3a
3b
17
19
20
26
25
30
34
24
25
27
29
28
32
45
18
19
22
26
25
28
32
24
26
28
29
29
31
52
Streptomycin (Standard)
spectrometer in CDCl3 using TMS as an internal ref-
erence. The 31P NMR spectra were recorded on a
JEOL AL 300 MHz FT NMR spectrometer at 121.49
MHz in CDCl3 using TMS and 85% H3PO4 as internal
and external reference, respectively, at room temper-
ature. IR spectra were recorded on a Perkin–Elmer
577 grating spectrometer in KBr disks in the region
4000–425 cm−1. FAB mass spectra were recorded on
a JEOL SX 102/DA-6000 mass spectrometer. Chlo-
rine was estimated volumetrically by using Volhard’s
method. Phosphorus was estimated as ammonium
phosphomolybdate. The molecular weights were de-
termined by using the Rast Camphor method.
closed sintered funnel. It was then concentrated to
one fourth of its volume under reduced pressure and
was kept in a vacuum desiccator to obtain crystals.
Recrystallization was done in dry ethanol.
Synthesis of S-(Phenyl Benzothiazolyl-2)O,O-
di(4-nitrophenyl)thiophosphate
2a/phosphorodithioate 2b
A solution of 4-nitrophenol (0.002 mol) in dry
THF was added dropwise with continuous stir-
ring in a solution of S-(phenyl benzothiazolyl-
2) phosphorodichloridothioate/phosphoro-dichlori-
ododithioate (0.001 mol) in THF and Et3N
(0.002 mol) in dry THF. The mixture was refluxed
for 14–16 h. Then the reaction was carried out in a
similar manner as described above.
Synthesis of S-(Phenyl Benzothiazolyl-2)O,O-
(diphenyl)thiophosphate 1a/phosphorodithioate
1b
A solution of phenol (0.002 mol) in dry THF was
added dropwise with continuous stirring in a solu-
tion of S-(phenyl benzothiazolyl-2) phosphorodich-
loridothioate/phosphorodichloridodithioate (0.001
mol) in THF and Et3N (0.002 mol) in dry THF.
The mixture was refluxed for 14–16 h. Then, it was
cooled and Et3N·HCl formed was filtered off with a
Synthesis of S-(Phenyl Benzothiazolyl-2)O,O-
di(4-chlorophenyl)thiophosphate
3a/phosphorodithioate 3b
A solution of 4-chlorophenol (0.002 mol) in dry THF
was added dropwise with continuous stirring in
TABLE 6 Fungitoxic Screening Data of Organophosphate Phenoxy Derivatives (1a-1b, 2a-2b & 3a-3b)
Percentage Mycelial Inhibition
Aspergillus niger (ppm)
Fusarium oxysporium (ppm)
S.No.
Compound
50
200
50
200
1
2
3
4
5
6
1a
1b
2a
2b
3a
3b
22.8
42.6
24.4
47.3
32.2
50.4
87.0
80.4
85.4
86.2
87.6
92.1
92.2
100.0
24.6
47.8
26.3
53.2
36.6
60.1
76.0
71.2
80.4
76.5
84.4
78.9
91.9
100.0
Dithane M-45
Heteroatom Chemistry DOI 10.1002/hc

88 Jhajharia, Samota, and Seth
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The authors are thankful to the Head, Department
of Chemistry, University of Rajasthan, Jaipur, India
for providing necessary facilities to carry out this
research work. Priyanka Jhajharia is grateful to Uni-
versity Grants Commission, New Delhi, India for the
financial support in the form of Junior Research Fel-
low wide grant no. 10-2(5)/2006 (i)-E.U.II.
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Heteroatom Chemistry DOI 10.1002/hc