A single-step one pot synthesis of O,O′-dialkyl N,N-dialkylphosphoramidates from dialkylphosphites

Article abstract of DOI:10.1016/j.tetlet.2016.07.019

An efficient synthetic method has been developed to obtain chemical weapons convention (CWC)-related O,O′-dialkyl-N,N-dialkylphosphoramidates from dialkylphosphites using inorganic reagents (CuCl₂and Cs₂CO₃) at room temperature.

Full text of DOI:10.1016/j.tetlet.2016.07.019

Tetrahedron Letters 57 (2016) 3754–3756
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Tetrahedron Letters
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0
A single-step one pot synthesis of O,O -dialkyl N,N-
dialkylphosphoramidates from dialkylphosphites
a
a
a
a
b
Ajay Kumar Purohit , Deepak Pardasani , Ajeet Kumar , D. Raghavender Goud , Rajiv Jain ,
D. K. Dubey
a
a,
⇑
Vertox Laboratory, Defence Research and Development Establishment, Gwalior 474002, India
School of Studies in Chemistry, Jiwaji University, Gwalior 474 002, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method has been developed to obtain chemical weapons convention (CWC)-related
Received 15 June 2016
Revised 4 July 2016
Accepted 5 July 2016
Available online 6 July 2016
0
O,O -dialkyl-N,N-dialkylphosphoramidates from dialkylphosphites using inorganic reagents (CuCl
2
and
2 3
Cs CO ) at room temperature.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Chemical warfare agent
Chemical weapons convention
Tabun
Dialkylphosphite
Phosphoramidates
Organophosphorus compounds (OPCs) have attracted the atten-
tion of researchers because of their wide applications in industrial,
agricultural, biochemical, and medicinal areas.1,2 Phosphorami-
dates are abundant structural motifs widely present in natural
and synthetic compounds of various applications.3 Phosphorami-
dates are also important precursors for the synthesis of various
bioactive compounds serving as a motif for natural products, phos-
phonopeptides, amino acid analogs, prodrugs and pharmacological
Recently, Hayes et al. reported the use of CuI catalyst along with
secondary amine for the synthesis of phosphoramidates.17
However, this method was mostly applicable to aromatic phospho-
ramidates with limited success to aliphatic phosphoramidates
related to CWC. Secondly, it involves tedious work-up procedure
for the removal of excess amount of amine present in the reaction
mixture, which leads to lower yields as well as the introduction of
impurity to the desired product. Due to their wide utility and our
interest to develop rapid and efficient synthetic methods for
CWC related compounds, this study was aimed to develop an effi-
cient synthetic procedure for the mild and efficient synthesis of O,
4
,5
0
agents.
One such class of OPCs is the O,O -dialkyl N,N-
dialkylphosphoramidates (DADAPs), bearing following general
structures are included in the schedule 2B6 category of chemical
weapons convention (CWC)6 (Fig. 1).
,7
0
O -dialkyl N,N-dialkylphosphoramidates. Reactions that can be per-
DADAPs are often produced as side products during the synthe-
sis of chemical warfare agents such as Tabun and its analogs (all of
which belong to schedule 1A2 of CWC). Thus the phosphorami-
dates may be considered as indicators of production of 1A2 com-
pounds. The identification of DADAPs in a suspected sample is an
formed without elaborate procedure and in one-pot are highly
desired.
Recently, we have explored the usage of the combination of two
2
inorganic reagents such as CuCl and CsF for the synthesis of dia-
1
8
lkyl fluorophosphates. Prompted by the efficiency and easy
workup of inorganic reagents, here in we are reporting the synthe-
8
important component of the verification regime of the CWC.
Due to wide applications of DADAPs, their efficient synthesis is
0
sis of O,O -dialkyl N,N-dialkylphosphoramidates from dialkylphos-
highly desirable. Several methods are reported in literature for
phites by CuCl
literature methods available for the use of Cs
base in different functional group transformations.
2
and cesium carbonate (Cs
2
CO
3
)
.
There are several
the synthesis of DADAPs.9
–16
However, these methods have one
or another drawback such as low yields, long reaction time, harsh
reaction conditions, and use of hazardous materials.
CO as an inorganic
2
3
1
9–21
2 3
Cs CO is
not only soluble in various organic solvents, its efficiency is also
high in comparison to other inorganic base due to unprecedented
2
2
cesium effect. We envisaged that combination of electrophilic
substitution of hydrogen in dialkylphosphites by chlorine followed
⇑
Corresponding author. Tel.: +91 751 2233488; fax: +91 751 2341148.
E-mail address: dkdubey@rediffmail.com (D.K. Dubey).
http://dx.doi.org/10.1016/j.tetlet.2016.07.019
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

A. K. Purohit et al. / Tetrahedron Letters 57 (2016) 3754–3756
3755
R1
Table 1
O
Optimization of reaction conditions
N
P
OR3
Entry Time
(min)
Solvent
Metal
salt
Inorganic
base
Temp.
(°C)
Yield
(%)
R2
OR4
1
2
3
4
5
6
30
30
30
30
30
30
CHCl
3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
25
25
25
25
25
25
25
12
70
40
45
75
1
2
3
4
R , R , R and R = Methyl, Ethyl, Propyl and Isopropyl
CH
CH
2
Cl
CN
2
3
0
Figure 1. General structure of O,O -dialkyl N,N-dialkylphosphoramidates.
Toluene
THF
Ethyl
by the nucleophilic addition of an amine to the resulting dialkyl
chlorophosphate may lead to formation of DADAPs. By this proce-
dure, by products could be removed from reaction mixture by fil-
tration and desired products could be obtained without
chromatographic purification process. To the best of our knowl-
edge, combination of these reagents has not been reported for
the one-pot conversion of dialkylphosphites to O,O -dialkyl N,N-
dialkylphosphoramidates using CuCl
To optimize various reaction conditions such as solvent, tem-
perature, metal salt and time, a model reaction was performed
acetate
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
7
8
9
1
1
1
1
30
10
20
30
30
30
30
30
30
30
CuCl
2
Cs
2
CO
3
25
25
25
25
25
25
25
25
40
50
93
30
75
60
65
50
48
72
53
32
CuCl2
2
Cs CO3
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
2
2
2
2
2
2
2
2
Cs
Na
CO
NaHCO
2
CO
3
0
1
2
3
2
CO
3
K
2
3
3
0
KHCO
MgO
3
2
3
2
and Cs
2
CO
3
(Scheme 1).
14
1
1
5
6
Cs
Cs
2
CO
CO
3
2
3
by treating diethylphosphite with CuCl
Progress of the reaction was monitored by GC-MS and P{H}
NMR. Results are summarized in Table 1.
2
and inorganic base.
3
1
O
P
O
P
2
CuCl2
+
2 CuCl
+
HCl
Reaction Conditions: Diethyl phosphite, secondary amine (N,N-
H
OC
2
H
5
Cl
OC
2 5
H
diethyl amine), metal salt (CuCl
the mole ratio of 1:2:2:2.
Among the various solvents screened, acetone, acetonitrile and
ethyl acetate afforded good yields (entries 1–7, Table 1) and mini-
mum time required for the completion of reaction was found to be
2
) and inorganic base were used in
OC
2
H
5
OC
2 5
H
C
2 5
H
HN
2
Cs CO3
C
2 5
H
3
0 min (entries 7–9, Table 1). Highest yield of the desired product
was obtained when Cs CO was taken as inorganic base (entries 7
10–14, Table 1). Temperature also played an important role in
O
C
2 5
H
2
3
&
N
P
OC
2
H
5
+ CsCl
this reaction; lower yields were observed when the temperature
was increased to 50 °C (entries 14–16, Table 1). This may be due
to the highly volatile nature of used secondary amine.
Although this reaction is performed in single pot, it proceeds in
two successive steps.
C H
2 5
OC
2 5
H
0
Scheme 2. Reaction mechanism for the synthesis of O,O -diethyl N,N-
diethylphosphoramidate.
In the first step, hydrogen of dialkylphosphites is substituted by
Table 2
chlorine of CuCl
2
in an electrophilic displacement reaction. In the
0
Synthesis variety of O,O -dialkyl N,N-dialkylphosphoramidates
second step, the chloride of dialkylchlorophosphate is nucleophili-
cally substituted by secondary amine to give the phosphoramidate.
Putative reaction mechanism is depicted in Scheme 2.
The applicability of the method was tested on other analogs of
dialkylphosphites. Results summarized in Table 2 confirm the
applicability of the method to various dialkylphosphites for the
synthesis of phosphoramidates.
Reaction Conditions: Dialkylphosphite, secondary amine, metal
2 2 3
salt (CuCl ) and inorganic base (Cs CO ) were used in the mole
ratio of 1:2:2:2 the reactions were carried out in acetone at room
temperature (25 °C).
O
P
R 2
O
CuCl 2 , Cs CO3
2
OR 1
OR 1
H
N
P
H
N
R3
OR 1
1
OR 1
R2
R3
2
3
Entry
R1
R2
CH
R3
CH
Product
Time (min)
Yield (%)
1
2
3
.
.
.
CH
CH
CH
3
3
3
3
3
3a
3b
3c
3d
3e
3f
30
30
30
30
30
30
30
30
30
30
30
30
40
40
40
40
81
87
82
80
70
86
89
84
81
75
72
83
76
74
82
85
C
2
H
5
2 5
C H
3
i-C H
7
i-C H
3 7
4.
5.
CH3
3
n-C H7
n-C H7
3
The major advantage of this method is the operational simplic-
ity and product isolation. The desired product is isolated from the
reaction mixture simply by filtration of reaction mixture followed
by solvent evaporation. The use of inorganic reagents helps in
delivering clean product without any organic impurities and thus
the process required no chromatographic purification step.
In conclusion, we have developed an efficient method for the
C
C
C
C
C
C
C
n-C
n-C
i-C
i-C
i-C
2
2
2
2
2
2
2
H
5
H
5
H
5
H
5
H
5
H
5
H
5
n-C
n-C
3
H
H
7
i-C
n-C
3
H
H
3 7
7
6
7
8
9
.
.
.
.
3
7
3
i-C H
7
i-C
i-C
n-C H
3 7
3
H
H
7
3g
3h
3i
CH
3
3
7
C
2
H
5
10.
CH
CH
3
C
2
H
5
3j
1
1
1
1
1
1
1.
2.
3.
4.
5
3
n-C
C H
2 5
3
H
7
3k
3l
3
H
7
C
2
H
5
3
H
7
n-C
n-C
3
H
H
7
7
n-C
n-C
3
H
H
7
7
3m
3n
3o
3p
0
synthesis of O,O -dialkyl N,N’-dialkylphosphoramidates at room
3
H
7
3
3
3
H
H
7
7
C
2
H
5
C
C
2
H
5
6
3
n-C
3
H
7
2 5
H
R2
O
O
P
O
P
Cs
2
CO3
CuCl
2
H
OR3
Cl
OR3
N
P
OR3
R2
OR4
OR4
R
2
OR4
HN
temperature. Reactions are operationally simple, dispense haz-
ardous reagents, give excellent yields and clean products. These
virtues make this synthetic method an important contribution
for the synthesis of CWC related phosphoramidates.
R1
0
Scheme 1. Synthesis of O,O -dialkyl N,N-dialkylphosphoramidates.

3
756
A. K. Purohit et al. / Tetrahedron Letters 57 (2016) 3754–3756
Cadogan, J. I. G.; Mackie, R. K.; Maynard, J. A. J. Chem. Soc. 1967, 1356–1360.
9.
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19.
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2
1
961.
3
4
.
.
Engel, R. Chem. Rev. 1977, 77, 349–367.
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stirred suspension of CuCl (0.20 mol) and Cs CO (0.20 mol) in acetone
(20 mL) at room temperature. Followed by addition of diethylamine (0.20 mol)
in one shot. The reaction mixture was then stirred at room temperature for
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completion of the reaction the reaction mixture was filtered to remove the
precipitate by using filter paper. The white solid residue was washed with
2 ꢀ 5 mL dichloromethane. The filtrate and washing were combined and
excess solvent was removed by distillation followed by vacuum distillation to
get the desired product. The reaction was carried out in an efficient fume hood
and disposable latex gloves and safety goggles were worn as normal practice
during the complete reaction work up.
8
54–859.
1
5
.
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