Bioactive heterocyclic trithiophosphoric esters: Synthesis and bioactivity

Article abstract of DOI:10.1080/10426500701521761

Novel, heterocyclic derivatives of trithiophosphoric acid have been achieved through phosphorylation of quaternary salts of N-heterocycles with phosphorus trichloride, the iminohalophosphines, thus obtained in situ were subjected to nucleophilic substitut

Full text of DOI:10.1080/10426500701521761

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Bioactive Heterocyclic
Trithiophosphoric Esters:
Synthesis and Bioactivity
Vijaya Kabra a , Arpana Meel a , Sunita Mitharwal a &
Swaroop Singh b
a Department of Chemistry, University of Rajasthan,
Jaipur, India
b Durgapura Agricultural Research Centre, University
of Rajasthan, Jaipur, India
Version of record first published: 03 Dec 2007.
To cite this article: Vijaya Kabra , Arpana Meel , Sunita Mitharwal & Swaroop Singh
(2007): Bioactive Heterocyclic Trithiophosphoric Esters: Synthesis and Bioactivity,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:12, 2833-2842
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Phosphorus, Sulfur, and Silicon, 182:2833–2842, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701521761
Bioactive Heterocyclic Trithiophosphoric Esters:
Synthesis and Bioactivity
Vijaya Kabra
Arpana Meel
Sunita Mitharwal
Department of Chemistry, University of Rajasthan, Jaipur, India
Swaroop Singh
Durgapura Agricultural Research Centre, University of Rajasthan,
Jaipur, India
Novel, heterocyclic derivatives of trithiophosphoric acid have been achieved through
phosphorylation of quaternary salts of N-heterocycles with phosphorus trichloride,
the iminohalophosphines, thus obtained in situ were subjected to nucleophilic sub-
stitution with mercaptans in organic solvents in the presence of HCl acceptors,
preferably triethylamine. Synthesized derivatives exhibited potential insecticidal
behavior against a polyphagous insect Plutella xylostella (Diamond Backmoth).
Keywords Heterocyclic organothiophosphate insecticides; phosphorylation; trithio-
phosphatic esters
INTRODUCTION
The organic trithiophosphates have been reported as important
organophosphorus derivatives, which have been considered as
defoliants,1 insecticides,1 and inhibitors of steel corrosion.2 Tripathi
et al.3−5 have successfully used these esters as ligands for the syn-
thesis of metal complexes of Sb, Sn, and so on. These authors also
cited that interest in this chemistry as organo antimony derivatives
of dithiophosphate ligands is a result of their potential bioactivity, such
as antitumor.6,7
Received April 9, 2007; accepted May 24, 2007.
We are highly thankful to the Department of Chemistry, University of Rajasthan, for
recording a number of spectra and also for providing all necessary facilities. We are also
thankful to the Department of Entomogloy, Durgapura Agricultural Research Centre, for
carrying out insecticidal activity.
Address correspondence to Vijaya Kabra, Department of Chemistry, University of
Rajasthan, Jaipur 302 004, India. E-mail: sgkabra@sancharnet.in
2833

2834
V. Kabra et al.
In the literature, only few synthetic routes have been described for
organotrithiophosphates. Bliznyuk et al.8,9 and Mandelbaum et al.10
have prepared these derivatives by treating dialkylchlorothiophosphate
with thiophenols in presence of HCl acceptors.
In the present study, we have described a novel synthetic strategy
and bioactivity of eleven such derivatives incorporating different het-
erocyclic rings. The amalgamation of trithiophospho moiety with hete-
rocyclic ring was also expected to augment the bioactivity. In our pre-
vious publications,11−13 we have reported the synthesis and bioactivity
of different tris amidothiophosphates using different N-heterocycles as
starting material and phosphorus trichloride as phosphorylating agent.
RESULTS AND DISCUSSION
N-Alkyl-2-aminopyridin/thiazole/benzothiazole (1) were reacted with
different haloalkanes (2) in THF and generated the corresponding
N-alkyl-2-aminopyridinium/thiazolium/benzothiazolium halides (3).
These quaternary salts then were subjected to phosphorylation with
phosphorus trichloride (one equivalent) in presence of a weak base
triethylamine (two equivalents) in methylene chloride at 0–5◦C and
furnished the corresponding iminodichlorophosphines (4). This inter-
mediate was oxidized in situ with elemental sulfur (1/8 equivalent)
at ambient temperature and produced corresponding cycloiminylide-
namidothiophosphoryl dichlorides (5), which on further substitution
with 2-propanethiol (two equivalents) at 0–5◦C gave the corresponding
products 6 (Scheme 1).
All the synthesized products were white crystalline solids, having
sharp melting points and were characterized by 1H, 31P and 13C NMR
techniques. All physical and spectral data have been reported in Tables I
and II, respectively.
31P NMR
The reaction course on monitoring showed a change in 31P signal
from 220 δppm (signal for PCl3) to 146–158 δppm (signal for tricoor-
dinated phosphorus) when phosphorus trichloride and triethylamine
were added to corresponding salt solutions. But addition of sulfur
shifted this signal in upfield region 38–80.6 δppm, which is characteris-
tic for compounds containing phosphorus in tetracoordinated state thus
confirming the completion of reaction. Pure solids 6a–k have shown 31
signal in the range 40–82.78 δppm (Table II).
P

Bioactive Trithiophosphoric Esters
2835
SCHEME 1
1H NMR
All CH3 protons of SCH(CH3)2 moiety appeared as multiplet be-
tween 1.01–1.66 δppm, while both SCH protons gave two septates
individually—between 3.01–3.55 δppm and 3.21–3.66 δppm, respec-
tively. Position of both protons of SCH is different in space with respect
to P=S, therefore gave signals separately. One SCH proton which is
cis to sulfur got deshielded and appeared in downfield, while other one
gave septate in comparatively upfield due to its trans position with re-
spect to sulfur. All NCH2 and NCH3 protons of 6a–k gave singlet in its
expected characteristic region between 3.72–5.50 δppm.
In 6a–c, two protons of OCH2C6H5 gave singlet between 4.76–4.90
δppm, and in 6d, 6e two protons of OCH2CH3 gave quartet between
4.15–4.21 δppm. This is due to three-bond coupling with adjacent CH3
protons, while CH3 protons of OCH2CH3 were found to absorb in the

2836
V. Kabra et al.
TABLE I Physical Data of Compounds
Molecular
formula
(mol. weight)
Elemental analysis (%)
Compound
(S.N.)
M.P.
(◦C)
Yield
(%)
C
H
N
6a
6b
6c
6d
6e
6f
C18H25N2S4PO2
(460.65)
73
82
89
56
75
92
76
92
115
83
90
70
72
63
50
52
50
62
80
60
60
55
46.93
(46.81)
51.74
(51.73)
52.84
(51.90)
45.90
(45.45)
39.17
(39.12)
44.42
(44.40)
37.48
(37.42)
54.52
(54.50)
36.79
5.47
(5.43)
5.33
(5.32)
5.99
(5.90)
6.42
(6.48)
5.81
(5.80)
6.12
(6.11)
5.50
(5.50)
6.35
(6.03)
5.87
6.08
(6.01)
5.49
(5.43)
6.16
(6.11)
7.14
(7.01)
7.03
(7.00)
7.40
(7.39)
7.28
(722)
7.06
(7.00)
8.58
C22H27N2S4PO2
(510.71)
C20H27N2S3PO2
(454.62)
C15H25N2S3PO2
(392.55)
C
C
C
13H23N2S4PO2
(398.58)
14H23N2S3PO2
(378.52)
12H21N2S4PO2
(384.55)
6g
6h
6i
C18H25N2S3P
(396.58)
C
10H19N2S4P
(326.51)
(36.76)
44.65
(44.61)
44.97
(5.80)
5.62
(5.59)
6.60
(8.50)
7.44
(7.43)
31.20
(30.20)
6j
C
14H2N2S4P
(376.57)
6k
C12H21N2S3P
(320.48)
(44.92)
(6.59)
range 1.01–1.66 δppm merged with other methyl protons of SCH(CH3)2
moiety. In 6f, 6g, OCH3 protons gave singlet between 3.67–3.92 δppm.
All the heterocyclic protons appeared in expected aromatic region with
expected multiplicities together with the aromatic protons of phenyl
group of OCH2C6H5 (6a–c).
13C NMR
As was expected in 13C NMR, SCHCH3 carbon gave singlet in most
upfield region between 22.15–25.37 δppm, while both the SCH car-
bons gave singlet together between 37.49–55.86 δppm. NCH2 carbon
in 6a–h gave singlet between 48.23–112.54 δppm, while NCH3 car-
bon of 6i-k gave singlet between 45-88–112.46 δppm. OCH2 carbons
of 6a–e appeared between 53.68–67.30 δppm, while OCH3 carbon of
6f–g appeared between 52.58–65.36 δppm as singlet. Similarly CH3
carbon of OCH2CH3 in 6d, 6e gave singlet at 27.49 and 38.15 δppm,
respectively.

2837

2838

2839

2840
V. Kabra et al.
C-2 carbon of heterocyclic ring absorbed at most downfield region be-
tween 134.50–171.85 δppm with minimum intensity due to its quater-
nary nature. Similarly all carbons of aromatic ring appeared according
to their expected range.
Bioactivity
Four trithiophosphates—6a, 6d, 6k, 6h—have been screened for in-
secticidal activity against Plutella xylostella. Two doses of 0.05% and
0.025% have been arbitrarily selected for inoculation observation of in-
sect mortality; they have been recorded after one, three, five, seven, and
ten days of their introduction to the insect food. The results have been
analyzed statistically and reported in Table III (Fig. 1).
Compound 6a was found to be most potent in both the concentra-
tions and even has shown better insecticidal activity in comparison to
endosulfan. Compound 6d was at par with compound 6a, and this was
also found to be better than endosulfan.
Initially, except 6a, all other synthesized products have shown low
bioactivity after 1–3 days of treatment, but after 5 days, all compounds
have shown appreciable activity. This enhancement of activity after 3
days of treatment could be explained due to auto oxidation of P S bond
to P O bond in the course of time which is a reported factor.14 Out of four
compounds, 6a and 6d were found to be most bioactive. If we consider
FIGURE 1 Percent mortality of Plutella xylostella 1, 3, 5, 7, and 10 days after
the treatment.

Bioactive Trithiophosphoric Esters
2841
structure versus reactivity relationship in both potent compounds 6a
and 6d, bulky and electron withdrawing groups have been attached to
NCH2 moiety; these two factors were reported to be the prerequisite
for a better insecticidal compound, which impaired the acetyl choline
esterase activity in the insect14 (Table III).
CONCLUSION
The present study has described a novel synthetic strategy for eleven
trithiophosphoric esters incorporating three different heterocycles
(pyridine, thiazole, and benzothiazole). Synthesized products 6a, 6d,
6h, 6k exhibited strong insecticidal activity against a polyphagous pest
Plutella xylostella. Even compound 6a and 6d were found to be better
in comparison to an established insecticide endosulfan.
EXPERIMENTAL
All the reactions were carried out in an inert atmosphere under ni-
trogen. All solvents and reagents were used after drying freshly. Fine
chemicals like 2-propanethiol, 2-aminopyridine, 2-amiothiazole, and 2-
aminobenzothiazole were procured from Merck and used as such. Glass-
wares were also dried very well by putting them into oven at high
temperature before using. Standard syringe technique was used for
adding the solvents and reagents. Since all the synthesized products
were highly hygroscopic in nature, we stored them under an inert at-
mosphere of nitrogen. Their melting points were determined by stan-
dard capillary method on electrictempo instrument. 31P NMR spectra
were recorded on Jeol AC300 at 121.50 MHz (Obset 156 KHz) using 85%
H3PO4 as external standard and 1H NMR spectra were recorded in Jeol
AL 300 at 300.4 MHz (Obset 130 KHz) using TMS as internal standard.
General Procedure of Synthesis of N-Substituted-2-
ylidenamido bis(S-isopropylthiol)thiophosphate (6a–k)
To the suspension of N-alkyl-2-pyridinium/thiazolium/benzothiazolium
halides (10.12 mmol) in methylene chloride, addition of triethylamine
(20.24 mmol) and phosphorus trichloride (10.12 mmol) was done at am-
bient temperature. After 24 h of stirring, 2-propanethiol (20.24 mmol)
in methylene chloride was added dropwise in presence of triethylamine
(20.24 mmol) at 0–5◦C temperature. The stirring continued for the next
60–65 h. After that the solvent was dried under vacuo, and the residue
was extracted with diethylether and left in refrigerator, whereupon a
white solid was separated out that was filtered and dried.

2842
V. Kabra et al.
Bioactivity
Two concentrations 0.05% (0.05 g was dissolved in 1–2 ml of acetone
and was made up with distilled water up to 1000 ml) and 0.025% (0.025
g was dissolved in 1–2 ml of acetone and was made up with distilled
water up to 1000 ml) of test compounds were given to the second instar
larval stage of insect by food dipping method.15,16 For control only ace-
tone and water mixture have been used. For standard 0.05% solution
of endosulfan was also prepared in similar way. Twenty insects were
kept together in a separate container and four such replicates were
prepared for each concentration of each compound. Percent mortality
of each replicate were calculated and then converted into angular trans-
formed values, which were then subjected to the statistical analysis of
completely randomized design (CRD) technique.17
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