Thionation of phosphoramidodichloridates and phosphoramidate diesters using phosphorus pentasulfide and hexamethyldisiloxane under microwave irradiation. Part 1

Article abstract of DOI:10.1016/j.tetlet.2004.07.099

A new, mild, efficient, and solvent-free microwave promoted synthesis of thiophosphoramidodichloridates and thiophosphoramidate diesters is described. The thionation reaction was accelerated with microwave irradiation using the combination of P₄S₁₀ and HMDO. The conversion of PO to PS by this method gave the desired product in higher yields and shorter reaction times as compared to conventional methods.

Full text of DOI:10.1016/j.tetlet.2004.07.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6863–6866
Thionation of phosphoramidodichloridates and phosphoramidate
diesters using phosphorus pentasulfide and
hexamethyldisiloxane under microwave irradiation. Part 1
Manisha Nivsarkar, Arvind K. Gupta and Mahabir P. Kaushik*
Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474002, MP, India
Received 17 June 2004;revised 14 July 2004;accepted 22 July 2004
Abstract—A new, mild, efficient, and solvent-free microwave promoted synthesis of thiophosphoramidodichloridates and thio-
phosphoramidate diesters is described. The thionation reaction was accelerated with microwave irradiation using the combination
of P4S10 and HMDO. The conversion of P@O to P@S by this method gave the desired product in higher yields and shorter reaction
times as compared to conventional methods.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Thiophosphoramidodichloridates are important inter-
mediates for the synthesis of various biologically active
organophosphorus compounds. Many of the syntheses
of phosphoramidates and their thio analogues depend
upon the availability of such compounds as the phos-
phorus chlorine bond is easily replaced with dialkyl or
diarylamino groups. For this reason, about ninety per-
cent of the commercially known pesticides make use of
this synthetic strategy in their manufacturing processes.1
Thiophosphoramidate diesters are also reported to have
activity at the commercial level in the major pesticide
areas, and are currently most prominent as insecticides,2
fungicides,3 and herbicides.4 They play a very important
role in various biological processes,1,5 and are also used
as chiral phosphorus auxiliaries in the asymmetric syn-
thesis of various organic compounds.6
phosphorus pentasulfide,10 and LawessonÕs reagent12
(LR), but only two deserve mention here as convenient
laboratory methods.10,12 The most commonly used
method for the direct conversion of P@O to P@S is
the high temperature reaction (100–150ꢁC) of phospho-
rus pentasulfide with phosphoramidates, which invaria-
bly results in contamination by the starting material and
also in the formation of several by-products. The second
route not only makes use of high temperatures but also a
less easily workable and costly reagent,12 which in turn
results in lower yields of the desired products. Recently
Curphey,13–15 has shown that a combination of P4S10
and HMDO as a thionating agent efficiently converts es-
ters, lactones, amides, and ketones into their thio deriv-
atives. Although the reported method is good in terms
of selectivity under standard conditions (dry toluene/xyl-
ene, thermal heating), the use of P4S10 and HMDO
under microwave conditions has provided an increase
in the selectivity and yields of the organophosphorus
compounds. Lizzani-Cuvelier and co-workers16 have
also reported the synthesis of thio c-lactones by making
use of a new combination of LawessonÕs reagent and
hexamethyldisiloxane (HMDO) in solvent-free condi-
tions under microwave irradiation. Nevertheless there
are, to our knowledge no reports dealing with the
synthesis of thio-analogues of organophosphorus com-
pounds under microwave irradiation. We were inter-
ested in a procedure, which would allow us easily to
prepare the thiophosphoramidodichloridates and thio-
phosphoramidate diesters, since such compounds are
An unusual fish toxin isolated from the red tide dino-
flagellate Ptychodiscus brevis was also found to have a
phosphoramidate as an active moiety in its structure.7
Several methods have been reported in the literature,8–12
which make use of various thionating agents (either
alone or in combination) such as elemental sulfur,11
Keywords: Phosphoramidodichloridates;Phosphoramidate diesters;
Solvent-free;Phosphorus pentasulfide;HMDO;Microwave irradia-
tion.
*
Corresponding author. Tel.: +91-751-2343972;fax: +91-751-
2341148;e-mail: mpkaushik@rediffmail.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.099

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M. Nivsarkar et al. / Tetrahedron Letters 45 (2004) 6863–6866
intermediates in synthetic routes to various biologically
active compounds.
Various phosphoramidodichloridates and phosphoram-
idate diesters were treated with different mole ratios of
P4S10, hexamethyldisiloxane (HMDO) at different
microwave powers. We found that phosphoramidodich-
loridates/phosphoramidate diesters, P4S10, and HMDO
in a mmol ratio of 1:0.8:1.5 at 900W are the appropriate
mole ratios to obtain maximum yields of the desired
products. For these studies a microwave oven (Samsung
CE 2977N operating at 2450MHz with an oven cavity
of 336 · 241 · 349mm and 28L volume) at a power level
of 900W, equipped with inverter technology that pro-
vide better control of the MW power was used. The
mixture of phosphoramidodichloridates and phosphor-
amidate diesters, P4S10, and HMDO was exposed to
microwave irradiation with intermittent heating and
mixing, to obtain better yields and cleaner products.
Intermittent heating reduces the formation of hot spots.
It was observed that, at elevated power levels, partial
decomposition or charring of the reaction mixtures
occurred possibly due to localized overheating. At the
end of the reaction, the internal temperature reached
110ꢁC. Under the above conditions various phosphor-
amidodichloridates and phosphoramidate diesters were
examined and the results are shown in Table 1.
S
P
O
P
R
R
Cl
Cl
Cl
Cl
P4S10
MW (900 W)
HMDO
N
N
R'
R'
S
P
O
RO
P4S10
MW (900 W)
RO
RO
HMDO
P
NHR'
NHR'
RO
Where R and R1 = alkyl, aryl
Microwave activation as a nonconventional energy
source has been an increasingly popular method that
can be used to carry out a variety of reactions within
short reaction times and with high yields and selectiv-
ity.17,18 Microwave irradiation increases the dipole–
dipole interactions with the polar molecules and can
reduce the activation energy.17 This method also reduces
thermal degradation by-products and takes place in the
absence of solvent.19–22
Table 1. Thionation of phosphoramidodichloridates and phosphoramidate diesters with P4S10 and HMDO under microwave irradiation at 900W
using the optimized conditions
Entry
1
Substrate
MW heating time (s)a
Product
Yield (%)b
89
O
S
8 · 30
(H3C)2N P(Cl)2
(H3C)2N P(Cl)2
O
S
2
8 · 30
90
(C2H5)2N P(Cl)2
(C2H5)2N P(Cl)2
O
S
3
4
5
8 · 30
8 · 30
8 · 30
92
90
92
(nC3H7)2N P(Cl)2
(nC3H7)2N P(Cl)2
O
S
(iC3H7)2N P(Cl)2
(iC3H7)2N P(Cl)2
O
S
(nC4H9)2N P(Cl)2
(nC4H9)2N P(Cl)2
O
S
H3C
H3C
6
7
8
8 · 30
8 · 30
8 · 30
88
90
92
N
P(Cl)2
N
P(Cl)2
C2H5
C2H5
O
S
H3C
H3C
N
P(Cl)2
N
P(Cl)2
nC3H7
nC3H7
O
S
H3C
H3C
N
P(Cl)2
N
N
P(Cl)2
iC3H7
iC3H7
O
S
C2H5
C2H5
9
8 · 30
8 · 30
90
90
90
N
P(Cl)2
P(Cl)2
iC3H7
iC3H7
O
S
C2H5
C2H5
10
11
N
P(Cl)2
N
P(Cl)2
nC3H7
nC3H7
O
S
16 · 30
(C6H5O)2P NH-C8H15
(C6H5O)2P NH-C8H15

M. Nivsarkar et al. / Tetrahedron Letters 45 (2004) 6863–6866
6865
Table 1 (continued)
Entry
Substrate
MW heating time (s)a
Product
Yield (%)b
S
O
12
13
16 · 30
16 · 30
86
85
(C6H5O)2P NH-C8H17
O
(C6H5O)2P NH-C8H17
S
(C6H5O)2P NH-C6H11
(C6H5O)2P NH-C6H11
O
S
14
15
16 · 30
20 · 30
82
84
(C6H5O)2P NH-C12H23
(C6H5O)2P NH-C12H23
S
H
O
H
(C6H5O)2P N
(C6H5O)2P N
O
S
16
17
20 · 30
12 · 30
87
89
(H3CO)2P NH-C8H15
(H3CO)2P NH-C8H15
O
S
(C3H7O)2P NH-C6H11
(C3H7O)2P NH-C6H11
All compounds demonstrated satisfactory IR, NMR (1H and 31P), and MS data and were compared with literature values as well as with authentic
samples.
a Number of irradiations for a given time;8 · 30 indicates eight irradiations of 30s each.
b Isolated yield.
In order to confirm the microwave effect on the reaction,
comparative studies were carried out by examining one
representative example each of phosphoramidodichlori-
dates and phosphoramidate diesters (entries 1 and 13)
under microwave as well as under conventional heating
using the same mole ratios of the reactants. Under
microwave irradiation, the reactions were complete in
4 and 8min as compared to 3 and 5h, with conventional
heating, respectively. With conventional heating the
conversion of phosphoramidodichloridate (entry 1) in
4min was only 12% complete as compared with 89% un-
der microwave irradiation. Similarly the conversion of
the phosphoramidate diester (entry 13) under conven-
tional heating in 8min was only 14% complete as com-
pared to 90% under microwave irradiation. Thus, it
was confirmed that microwave heating has advantages
in terms of reaction times and product yield over the
conventional heating method. Using the conventional
method, the transformation is effected at higher temper-
atures (100–150ꢁC), for long periods of time (4–10h).
The conventional method also involves a tedious work
up giving poor to moderate yields.
power was also varied and reactions were conducted at
100, 180, 300, 450, 600, and 900W using the substrates
from entries 1 and 13. We observed that at 900W, the
time taken for complete conversion was less and yields
were also very high. Furthermore, if the reaction time
was increased, then decomposition took place. This re-
sulted in reduced yields of the desired products and
work up also became tedious.
In conclusion, we have developed a new and useful pro-
cedure, which is very effective for the synthesis of vari-
ous organophosphorus compounds and which can be
easily scaled up to large quantities. Further synthetic
utility of this thionating procedure with other organic
substrates is currently under investigation.
Acknowledgements
We thank Shri. K. Sekhar, Director, and DRDE Gwal-
ior for his keen interest and encouragement.
In order to evaluate the influence of HMDO, reactions
(entries 1 and 13) were also carried out in the absence
of HMDO under the same conditions. We found that
the reaction time increased from 4 to 25 and from 8 to
30min, respectively. The yields of the products also de-
creased by 10–12 percent. This clearly shows that
HMDO plays an important role. Many factors such as
a change in the alkyl group of the phosphoramidate
diesters, microwave power, and reaction time also have
profound effects on the progress of the reaction. The
reactivity of phosphoramidate diesters (entries 11–15)
is less comparatively than that of N,N-dialkylphospho-
ramidodichloridates. This may be due to the greater lyo-
phobic character of the phenyl and b-naphthyl groups,
which reduce dipole–dipole interactions.17 Microwave
References and notes
1. Eto, M. Organophosphorous Pesticides: Organic and Bio-
logical Chemistry;CRC: Cleveland, Ohio, 1974.
2. Ohkawa, H.;Mikami, N.;Miyamoto, A.
Chem. 1975, 39, 2265.
3. Spencer, E. Y. Guide to the Chemicals Used in Crop
Protection, 6th ed.;Research Branch Agriculture: Canada,
1973.
4. Chiriac, A.;Simon, Z.;Chiriac, V.;Vilceanu, R.;Timiso-
ara, U. [Prepr.] Sect. Chim. 1976, 10, 12, Chem. Abstr. 89,
101611t.
J. Agr. Biol.
5. Fest, C.;Schmidt, K. J. The Chemistry of Organophos-
phorous Pesticides;Springer: Berlin, Heidelberg, New
York, 1982.
6. Molt, O.;Schrader, T. Synthesis 2002, 2633.

6866
M. Nivsarkar et al. / Tetrahedron Letters 45 (2004) 6863–6866
7. Di Novi, M.;Trainor, D. A.;Nakanishi, K. Tetrahedron
Lett. 1983, 24, 855.
21. Deshayes, S.;Liagre, M.;Loupy, A.;Luche, J. L.;Petit, A.
Tetrahedron 1999, 55, 10851.
8. Tolkmith, H. J. Org. Chem. 1958, 23, 1682.
9. Godovikov, N. N.;Kabachnik, M. I. Zh. Obshch. Khim.
1961, 31, 1628.
10. Maier, L. Helv. Chim. Acta 1965, 48, 133.
11. Fild, M.;Schmutzler, R. In Organo Phosphorous Com-
pounds;Kosolapoff, G. M., Maier, L., Eds.;Wiley: New
York, 1972;Vol. 4, Chapter 9.
12. Maier, L. Helv. Chim. Acta 1963, 46, 2026.
13. Curphey, T. J. Tetrahedron Lett. 2002, 43, 371.
14. Curphey, T. J. Tetrahedron Lett. 2000, 41, 9963.
15. Curphey, T. J. J. Org. Chem. 2002, 67, 6461.
16. Filippi, J. J.;Fernandez, X.;Lizzani-Cuvelier, L.;Loiseau,
A. M. Tetrahedron Lett. 2003, 44, 6647.
17. Perreux, L.;Loupy, A. Tetrahedron 2001, 57, 9199.
18. Blackwell, H. E. Org. Biomol. Chem. 2003, 1, 1251.
19. Loupy, A.;Petit, A.;Hamelin, F.;Texier-Boullet, F.;
Jacqualt, P.;Mathe, D. Synthesis 1998, 1213.
20. Varma, R. S. Green Chem. 1999, 1, 43.
22. Rodriguez, H.;Perez, R.;Suarez, M.;Law, A.;Cabrales,
N.;Loupy, A. Heterocycles 2001, 55, 291.
Typical procedure: Phosphoramidodichloridates and
phosphoramidate diesters7 (1.0mmol), P4S10 (0.8mmol),
and HMDO (1.5mmol) were taken in a 250mL conical
flask and mixed thoroughly on a cyclomixer. After initial
exposure for 30s in a MW oven at a power level of 900W,
the flask was taken out, shaken for 10s and then exposed
to the same MW power for further periods of time as
indicated in Table 1 until the formation of the thio
compounds was virtually complete. The recorded internal
temperature of the reaction mixture was 110ꢁC. The
progress of the reaction was monitored by TLC (silica
plates, 10% acetone in toluene) and GC. After the
completion of reaction, the reaction mixture was dissolved
in dichloromethane, filtered, concentrated, and purified by
column chromatography (silica 60–120mesh), using tolu-
ene as the eluent.