Mild and efficient esterification of alkylphosphonic acids using polymer-bound triphenylphosphine

Article abstract of DOI:10.1016/j.tetlet.2012.05.045

Mild and efficient esterification of alkylphosphonic acids using primary alcohols, iodine, imidazole and polymer-bound triphenylphosphine is developed.

Full text of DOI:10.1016/j.tetlet.2012.05.045

Tetrahedron Letters 53 (2012) 3795–3797
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Mild and efficient esterification of alkylphosphonic acids using
polymer-bound triphenylphosphine
Ajay Kumar Purohit a, Deepak Pardasani a, Vijay Tak a, Ajeet Kumar a, Rajeev Jain b,
Devendra Kumar Dubey a,
⇑
a Vertox Laboratory, Defence Research & Development Establishment, Jhansi Road, Gwalior 474 002, India
b School of Studies in Chemistry, Jiwaji University, Gwalior 474 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Mild and efficient esterification of alkylphosphonic acids using primary alcohols, iodine, imidazole and
polymer-bound triphenylphosphine is developed.
Received 9 March 2012
Revised 8 May 2012
Accepted 10 May 2012
Available online 17 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iodine
Imidazole
Polymer-bound triphenylphosphine
Alkylphosphonic acids
O,O0-Dialkyl alkylphosphonates
Esters of alkylphosphonic acids are of particular importance due
to their synthetic and pharmaceuticals applications.1,2 Besides
their useful applications, esters of alkyl (methyl, ethyl, i-propyl
and n-propyl) phosphonic acids are also registered as extremely
toxic nerve agents.3,4 Considering the threat from nerve agents,
which form a major class of chemical warfare agents (CWAs), their
proliferation is prohibited by an international treaty known as
Chemical Weapons Convention (CWC). CWC is administered by
an international organisation known as Organisation for Prohibi-
tion of Chemical Weapons (OPCW).5–7 OPCW administers CWC
through its verification regime.
formation of alkylphosphonic dichlorides by the use of corrosive
and environmentally harmful thionylchloride (SOCl2) from alkyl-
O
P
O
P
OH
OH
OC5H11
OC5H11
I2, Imidazole
PPh2
HOC5H11
+
H3C
H3C
Figure 1. Esterification of methylphosphonic acid.
One component of verification programme of CWC, dealing
with the off-site analysis, requires O,O0-dialkyl alkylphosphonates
(DAPs) as reference chemicals for identification of the chemicals
related to CWC.8 DAPs are included in the schedule 2B4 category
of CWC and most of them are commercially not available. Hence,
their synthesis becomes an inevitable activity during verification
analysis. These compounds are synthesised by the laboratories in-
volved in international proficiency tests conducted by the OPCW.8,9
Variety of reactions are reported in the literature for the synthesis
of DAPs.8,10–13 Two approaches are noteworthy, (i) condensation of
alkylphosphonic dichlorides with alcohols in the presence of
base13,14 and (ii) condensation of alkylphosphonic acids with
alcohols aided by carbodiimide.8 Former method requires the
Table 1
Formation of O,O0-dipentyl methylphosphonatea from methylphosphonic acid and n-
pentanol as per Gareg–Samuelsson reaction in different solvents
Entry
Solvents
Yieldb (%)
1
2
3
4
5
6
7
Dichloromethane
Chloroform
Hexane
Benzene
Toluene
94
90
85
32
15
12
10
Ethyl acetate
Acetonitrile
a
Reaction conditions: Methyl phosphonic acid (1.0 mmol), iodine (3 mmol),
imidazole (6.6 mmol), polymer-bound triphenylphosphine (3 mmol) and alcohol
(2.5 mmol) reaction time 50 min.
⇑
Corresponding author.
E-mail address: dkdubey@rediffmail.com (D.K. Dubey).
b
Isolated yield.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.045

3796
A. K. Purohit et al. / Tetrahedron Letters 53 (2012) 3795–3797
Table 2
Condensation of alkylphosphonic acid with alcohols in the presence of iodine, imidazole and polymer-bound triphenylphosphine
Entry
R
R0
Producta
Time in minutes
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C3H7
C3H7
C3H7
CH3
C3H7
O,O0-Dimethyl methylphosphonate
O,O0-Dipropyl methylphosphonate
O,O0-Dipentyl methylphosphonate
O,O0-Didecyl methylphosphonate
O,O0-Diethyl ethylphosphonate
O,O0-Dipentyl ethylphosphonate
O,O0-Didecyl ethylphosphonate
O,O0-Dimethyl propylphosphonate
O,O0-Dipentyl propylphosphonate
O,O0-Didecyl propylphosphonate
40
45
50
60
45
50
60
40
50
60
85
90
94
82
90
92
84
87
92
83
C5H11
C10H21
C2H5
C5H11
C10H21
CH3
C5H11
C10H21
a
Reaction conditions: alkyl phosphonic acid (1.0 mmol), iodine (3 mmol), imidazole (6.6 mmol), polymer-bound triphenylphosphine (3 mmol)
and alcohol (2.5 mmol).
b
Isolated yield.
oxide could be removed by simple filtration thereby avoiding the
chromatographic purification.
O
P
OR'
OR'
O
P
OH
OH
I2, Imidazole
PPh2
R'OH
To optimise the reaction conditions such as time, temperature
and solvent, condensation of methylphosphonic acid with n-pent-
anol (as a pilot reaction) was performed in the presence of imidaz-
ole, iodine (I2) and polymer-bound triphenylphosphine (Fig. 1)
Reaction was performed as per details presented in the experi-
mental section and O,O0-dipentyl methylphosphonate was ob-
tained in excellent yield at 45–50 °C within 50 min. The effect of
solvent on yield was also studied and results are summarised in
Table 1
+
R
R
Figure 2. Esterification of alkylphosphonic acid.
phosphonic acids and latter method generates DAPs with side
products requiring chromatographic purification.8
It is evident from these results that best yields were obtained in
dichloromethane or chloroform. Therefore, further reactions were
performed in dichloromethane with different alkylphosphonic
acids and alcohols. Results of these reactions are presented in Table
2. Reactions afforded all esters in excellent yields; the noteworthy
point is that alcohols C1–C10 reacted with almost equal efficiency
under the employed reaction conditions (Fig. 2). Whereas conden-
sations of alkylphosphonic dichlorides with higher alcohols (C5–
Recently, esterification of carboxylic acid is reported by exploit-
ing Garegg–Samuelsson reaction.15 In this reaction, an efficient
esterification of carboxylic acids by the intermediacy of phospho-
nium-carboxylate salt was achieved by using triphenylphosphine,
iodine and imidazole. In this reaction, purification of synthesised
esters, required chromatographic removal of triphenylphosphine
oxide. Recently, the use of polymer-bound triphenylphosphine
has been reported for the synthesis of olefins and aryl ethers,
and its use as dehydrating reagent is also documented.16–18 To
the best of our knowledge, so far this reaction is not reported for
the synthesis of phosphorous esters that is O,O0-dialkyl
alkylphosphonates. Promoted by the efficiency and mildness of
the reaction and given the scope for improvement by use of com-
mercially available polymer-bound triphenylphosphine, we ex-
plored this reaction for synthesis of DAPs.19 We envisaged that
after completion of reaction, the byproduct triphenylphosphine
C10) produce less yields with the formation of pyrophosphonates
as side products.11 The important feature of reaction is isolation
of final product from the reaction mixture. As stated in experimen-
tal section, after completion of reaction, the polymer-bound tri-
phenylphosphine oxide and imidazolium iodide were removed
by filtration and the product was obtained from dichloromethane
after removing the solvent by distillation. Further purification of
crude product was done by vacuum distillation.
I-
P+Ph2I
P+Ph2
PPh2
+
+
I2
I-
+
H
I-
P+Ph2I
N
N
+HI
+
N
N
I-
O
P
I-
+
I-
O
P
OPh2P+
OPh2P+
OH
+
OH
P+Ph2
2
R
NH
2
N
R
N
N
OPh2P+
I-
+
I-
O
P
OR'
O
P
2
+ 2 OH-R'
HN
+ 2
R
+ 2 OPh2P
R
NH
N+H I-
N
OR'
OPh2P+
P
PPh2
=
Scheme 1. Mechanistic proposal for the esterification of phosphonic acids by using iodine, imidazole and polymer-bound triphenylphosphine.

A. K. Purohit et al. / Tetrahedron Letters 53 (2012) 3795–3797
3797
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alkylphosphonic acid and polymer-bound triphenylphosphine are
formed as per the scheme presented in Scheme 1. This salt under-
goes nucleophilic attack by alcohol, generating DAPs and releasing
polymer-bound triphenylphosphine oxide and imidazolium iodide.
When more hindered secondary alcohols were used in this reac-
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propyl alcohol gave rise to 30–35% yield in comparison to the
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In conclusion, we have developed an efficient and convenient
method for the synthesis of a variety of O,O0-dialkyl alkylphospho-
nates from corresponding alkylphosphonic acids using polymer-
bound triphenylphosphine. Main feature of this reaction is removal
of triphenylphosphine oxide by simple filtration, as polymer-
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