Efficient and convenient one-pot synthesis of phosphoramidates and phosphates

Article abstract of DOI:10.1080/00397910701483662

A simple and efficient one-pot method is described for the synthesis of phosphoramidates/phosphates in excellent yields from dialkylphosphites and trichloroisocyanuric acid in acetonitrile and subsequent treatment with dialkyl amines/alcohols. The procedure is operationally simple, has reduced reaction times, and uses a one-pot procedure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701483662

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Efficient and Convenient One‐Pot Synthesis of
Phosphoramidates and Phosphates
a
a
a
a
A. K. Gupta , J. Acharya , D. K. Dubey & M. P. Kaushik
a
Process Technology Development Division, Defence Research and
Development Establishment, Gwalior, M P, India
Available online: 05 Oct 2007
To cite this article: A. K. Gupta, J. Acharya, D. K. Dubey & M. P. Kaushik (2007): Efficient and Convenient
One‐Pot Synthesis of Phosphoramidates and Phosphates, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 37:19, 3403-3407
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Synthetic Communications , 37: 3403–3407, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701483662
Efficient and Convenient One-Pot Synthesis
of Phosphoramidates and Phosphates
A. K. Gupta, J. Acharya, D. K. Dubey, and M. P. Kaushik
Process Technology Development Division, Defence Research
and Development Establishment, Gwalior, India
Abstract: A simple and efficient one-pot method is described for the synthesis of
phosphoramidates/phosphates in excellent yields from dialkylphosphites and trichlor-
oisocyanuric acid in acetonitrile and subsequent treatment with dialkyl amines/
alcohols. The procedure is operationally simple, has reduced reaction times, and
uses a one-pot procedure.
Keywords: dialkylphosphites, phosphates, phosphoramidates, trichloroisocyanuric
acid
Phosphoramidates and phosphates are important for the synthesis of various
bioactive compounds serving as natural products, phosphates, phosphonopep-
tides, amino acids analogues, prodrugs, pharmacological agents and as
[
1–6]
0
important synthetic precursors.
Furthermore, O,O-dialkyl N,N -dialkyl-
phosphoraamidates (DADAPs) are also often produced when highly toxic
chemical warfare agents such as tabun and its analogues are prepared.
Amongst, the various procedures, two have been widely used in the labora-
tory. First is alcoholysis of phosphoramidic dichloride in presence of tertiary-
[
2,7]
0
amine.
phosphoramidic dichloride with sodium alkoxide.
The second method involves reaction of N,N -dialkyl
[8]
Herein, we report a rapid, efficient, economic, environmentally benign,
and easy to scale-up method for the effective conversion of O,O-dialkyl
Received February 5, 2007
Address correspondence to M. P. Kaushik, Process Technology Development
Division, Defence Research and Development Establishment, Jhansi Road, Gwalior
474002 M P, India. E-mail: mpkaushik@rediffmail.com
3
403

3
404
A. K. Gupta et al.
0
Scheme 1. One-pot synthesis of O,O-dialkyl N,N -dialkyl phosphoramidates from
dialkyl phosphites and dialkyl amines in, the presence of TCICA.
0
N,N - dialkylphosphoraamidates (DADAPs) from dialkylphosphites in the
presence of trichloroisocyanuric acid (TCICA) (Scheme 1) and Table 1.
Dialkylphosphites were condensed with various dialkyl amines (sym-
metrical and unsymmetrical) in presence of trichloroisocyanuric acid at 08C
and at room temperature. The room temperature (20–258C) reaction of
dialkyl phosphites with various amines in the presence of TCICA afforded
the corresponding phosphoramidates in 40–60 min with excellent yields
3
1
(
chlorophosphate appeared at d 4.14. The P NMR signal at d 4.14 disap-
Table 1). The results of P NMR studies indicated that signal of diethyl
3
1
peared after the addition of dipropyl amine and a new signal re-appeared at
0
a
Table 1. Synthesis of O,O-dialkyl N,N -dialkyl phosphoramidates
Phosphoramidates
3
1
b
P ppm
[9]
(lit)
Bp (8C/
mm Hg)
Yield
(%)
0
00
31
Entry
R
R
R
P ppm
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
14.10
11.42
11.50
9.35
14.15
11.48
11.54
9.32
82/6
84/5
92/3
92/1
98/1
110/1
118/1
116/1
96/1
110/2
114/1
108/1
96/1
112/1
124/1
120/1
92
86
82
85
80
82
79
84
88
CH
CH
3
3
CH
CH
3
3
2 5
C H
n
C
C H
3
H
7
7
7
i
CH3
CH3
3
7
C
C
2
H
H
5
5
5
5
C
C
2
H
H
5
5
5
5
CH
3
13.55
10.80
10.28
8.30
13.55
10.73
10.25
8.30
2
2
C
2
H
5
n
C H
2
C H
2
C H
3
i
C
2
H
C
2
H
C
3
H
7
n
n
C
C
3
H
H
7
7
7
7
C
C
3
H
H
7
7
7
7
CH
3
13.78
11.11
11.20
9.12
13.82
11.50
11.20
9.15
n
n
n
i
n
n
n
1
1
1
1
1
1
1
0
1
2
3
4
5
6
3
3
C
2
H
C H
5
n
C H
C H
86
91
89
86
87
91
3
3
3
i
C
3
H
C
3
H
3 7
C H
C
3
H
7
C
3
H
7
CH
C H
3
11.45
8.89
11.50
8.90
i
i
i
i
C H
C H
3
3
7
7
7
7
2
5
i
i
n
C
C
3
H
H
C
C
3
H
H
7
C
3
H
7
8.82
6.88
8.80
8.90
i
3
3
7
C
3
H
7
a
Reactions were carried out at ambient temperature, and the products had satisfac-
tory IR, NMR, and GC-MS data, which were compared with authentic samples and lit-
erature values.
b
31
3
Reactions were monitored by P NMR in CDCl at 400 MHz NMR.

Phosphoramidates and Phosphates
3405
Scheme 2. One-pot synthesis of phosphates.
d 10.28 within 30 min. It clearly demonstrated the conversion of diethylpho-
sphite to diethyl chlorophosphate followed by the formation of corresponding
0
O,O-diethyl N,N -dipropyl phosphoramidates. Filtration of heterogeneous
reaction mixture and concentration of the solvent provided the pure product
in 79% isolated yield (entry 7, Table 1).
To study the versatility of the method, few reactions of diphenyl
phosphite were also attempted (Scheme 2); corresponding phosphates were
obtained in high yields (Table 2).
In conclusion, we have developed a simple, rapid, economical and
efficient one-pot synthetic method for preparation of DADAPs and phosphates.
GENERAL EXPERIMENTAL PROCEDURE
In a typical experimental procedure, dialkylphosphite (0.01 mol) was added to
a solution of TCICA (0.0034 mol) in 10 mL of acetonitrile, and the reaction
mixture was stirred for 10–20 mins. The progress of the reaction mixture
Table 2. Synthesis of phosphates from diphenyl phosphite and alcohols in the pre-
sence of TCICA
3
1
31
Yield
b
(%)
Bp/
[DC(mmHg)]
P
(ppm)
P (ppm)
(lit.)
a
0
c
Entry
R
1
2
3
4
5
6
7
8
9
CH3
85
84
88
89
84
85
82
79
78
75
155(.2)
157(.1)
160(.1)
161(.1)
165(.1)
172(.1)
175(.2)
160(.2)
190(.1)
192(.1)
215.2
215.3
214.6
214.7
212.5
212.3
212.2
218.1
210.8
217.5
214.5
214.3
213.5
213.9
212.8
211.4
212.1
218.3
210.8
217.7
2 5
C H
n-C
i-C
n-C H
3
H
7
9
3
H
7
4
C
C
6
H
H
11
5
9
CH CHCH
2
2
Menthyl
1
0
6 5 2
C H CH
a
Reaction completes at reflux temperature for entries 5–10. All compounds
compared with authentic samples and characterized by IR, NMR, and MS.
b
Isolated yield.
c31
3
P NMR spectra were recorded in CDCl at 400 MHz.

3
406
A. K. Gupta et al.
3
was monitored by P NMR by drawing a few milligrams of the reaction
1
3
1
mixture in a NMR tube. The results of NMR studies indicate that the
P
NMR signal of dialkylphosphites is exchanged by a corresponding dialkyl-
chlorophosphate. It is also physically visualized by appearance of a white
amorphous precipitate of cyanuric acid. The reaction mixture was diluted
with 10 ml of dry ether and cooled at 08C with stirring. A mixture of
dialkyl amine and triethyl amine (0.02 mol each) was added slowly with
stirring at room temperature. The progress of the reaction was further
3
1
31
monitored by P NMR. The results of NMR studies indicate that P NMR
signal of corresponding dialkylchlorophosphate completely disappeared, and
a new signal of phosphoramidates appeared within 30 min. The reaction
mixture was filtered; after removal of solvent, the product was distilled
under vacuum to get pure DADAP.
ACKNOWLEDGMENTS
We thank Shri K. Sekhar, director, DRDE, Gwalior, for his keen interest and
encouragement. The authors are also thankful to Mamta Sharma for NMR
analysis and D. Pardasani for GC-MS analysis.
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