A single-step one pot synthesis of dialkyl fluorophosphates from dialkylphosphites

Article abstract of DOI:10.1016/j.tetlet.2015.06.014

An efficient synthetic method has been developed to obtain dialkyl fluorophosphates from dialkylphosphites using inorganic reagent (CuCl₂ and CsF) at room temperature.

Full text of DOI:10.1016/j.tetlet.2015.06.014

Accepted Manuscript
A single–step one pot synthesis of dialkyl fluorophosphates from dialkylphos-
phites
Ajay Kumar Purohit, Deepak Pardasani, Ajeet Kumar, D. Raghavender Goud,
Rajiv Jain, D.K. Dubey
PII:
S0040-4039(15)00995-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.014
TETL 46406
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 April 2015
4 June 2015
5 June 2015
Please cite this article as: Purohit, A.K., Pardasani, D., Kumar, A., Raghavender Goud, D., Jain, R., Dubey, D.K.,
A single–step one pot synthesis of dialkyl fluorophosphates from dialkylphosphites, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.014
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Tetrahedron Letters
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A single–step one pot synthesis of dialkyl fluorophosphates from dialkylphosphites
Ajay Kumar Purohita, Deepak Pardasania, Ajeet Kumara, D. Raghavender Gouda, Rajiv Jainb and D.K. Dubeya,*
aVertox Laboratory, Defence Research and Development Establishment, Gwalior-474002, India.
b School of Studies in Chemistry, Jiwaji University, Gwalior- 474 002, India.
ARTICLE INFO
ABSTRACT
An efficient synthetic method has been developed to obtain dialkyl fluorophosphates from
dialkylphosphites using inorganic reagent (CuCl2 & CsF) at room temperature.
Article history:
Received
2009 Elsevier Ltd. All rights reserved
.
Received in revised form
Accepted
Available online
Keywords:
Dialkylphosphites
Dialkyl fluorophosphates
Cesium Flouride
Copper(II)Chloride
Organophosphorus-fluorine (OPF) compounds represent an
important class of organophosphrous compounds.1 The
physical, chemical and physiological properties of organic
molecules altered with the introduction of fluorinated group;
usually leading to increased stability and lipophilicity.2 In
addition, fluorine substitution can also enhance the metabolic
stability of pharmaceuticals.3 The OPF compounds are potent
inhibitors of enzyme like acetyl cholinesterase.4-5 Due to wide
applications of organophosphrous-fluorine compounds their
efficient synthesis is highly desirable.6 Several methods are
reported in literature for the synthesis of dialkyl
fluorophosphates.7-9 However, these methods have several
drawbacks such as multiple reaction steps, requirement of
excess amount of chlorinating reagent, limited applicability,
harsh reaction conditions, corrosive or moisture sensitive
reagents, requirement of inert atmosphere and formation of
side products leading to intricate reaction mixtures.7
Recently, Yang et.al reported the use of Cu (II) catalyst and
sodium fluoride along with 2,3-dichloro-5,6-dicyano-4-
benzoquinone (DDQ) as an oxidizing agent for the synthesis
of phosphoric fluoridates.10 However, this method was mostly
applicable to aromatic phosphites with limited success to
aliphatic phosphites. Secondly, use of DDQ as oxidizing
agent required post-reaction processing to obtain the
compounds in pure form. Considering the volatility and
toxicity of dialkyl fluorophosphates, a synthetic method is
highly desirable that can afford pure product without
exhaustive work up.
Herein we are reporting a simple and straight forward method
for the synthesis of dialkyl fluorophosphates. The clue for this
study was taken from earlier published work involving room
temperature conversion of dialkylphosphites to dialkyl
chlorophosphates using CuCl2.11 We envisaged that
combination of electrophilic substitution of hydrogen in
dialkylphosphites by chlorine followed by the nucleophilic
substitution of chloride by fluoride in dialkyl chlorophosphate
would yield dialkyl fluorophosphates. For execution of this
scheme, the combination of inorganic reagents CuCl2 and CsF
was resorted. By the use of this combination, reaction by
products could be removed from reaction mixture by
filtration, and desired products could be obtained in pure form
without requiring distillation or chromatographic purification.
To the best of our knowledge combination of these reagents
has not been reported as fluorinating agent for the one-pot
conversion of dialkylphosphites to dialkyl fluorophosphates
(Scheme 1).12
O
O
CuCl2
CsF
H
P
OC2H5
F
P
OC2H5
OC2H5
OC2H5
Scheme1. Synthesis of diethyl fluorophosphates
To optimize various reaction conditions such as solvent,
temperature, fluorinating agent, metal salts and time, (Figure
1)
a
model reaction was performed by treating
*Corresponding author. Tel.: +91-751-2233488;
fax: +91-751-2341148.
E-mail address: dkdubey@rediffmail.com (D.K.Dubey).
diethylphosphite with CuCl2 & CsF. Progress of the reaction
was monitored by GC-MS and 31P NMR. Results are
summarized in table 1.

2
Tetrahedron
O
O
P
Table 1 Optimization of reaction condition
CuCl2
HCl
CuCl
+
+
OC2H5
H
P
OC2H5
Cl
Entry Time
(Min)
Solvent
Metal Fluorinating Yield
(%)b
10
12
15
50
65
92
65
20
78
80
85
8
OC2H5
OC2H5
CsF
salt
Agent
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
NaF
KF
1
2
3
4
5
45
45
45
45
45
45
30
15
45
45
45
45
45
45
Chloroform
Acetonitrile
Toluene
CuCl2
CuCl2
CuCl2
Tetrahydrofuran CuCl2
O
Ethyl acetate
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuBr2
CuCl
CuBr
CuI
6
F
P
OC2H5
+
CsCl
7
8
9
10
11
12
13
14
OC2H5
Scheme 2. Reaction mechanism for the synthesis of diethyl
fluorophosphates.
CsF
CsF
CsF
CsF
When Cu (I) salts were taken instead of Cu (II), very poor
yields were obtained (entries 12-14, table 1). These
observations indicate the operation of the mechanism
suggested in above scheme. Thus, finally optimized reaction
conditions were CuCl2 and CsF as reagents, acetone as
solvent, reaction time 45 minutes and room temperature.
The applicability of the synthetic method was tested on other
analogs of dialkylphosphites. Results summarized in table 2
conform the applicability of the method to various
dialkylphosphites.
5
7
a
Reaction Conditions : Diethylphosphite, CuCl2 and CsF
were used in the mole ratio of 1:2:2 all the reactions were
carried out at room temperature.
b Isolated yield.
Table 2 Synthesis of dialkyl fluorophosphates / dialkyl
phosphinates.a
Yield (%)b
Entry
R
JP-F
1
2
3
4
5
6
7
8
OCH3
974.85
970.08
967.53
970.59
961.23
989.25
963.12
990.26
89
92
92
88
87
82
60
85
OC2H5
OiC3H7
OC4H9
OC5H11
OC6H11
OC6H13
C2H5
a: Diethyphosphite , b: Diethyl fluorophosphate c: Tributyl
phosphate as internal standard
Figure 1. 31P {H} NMR spectra of the individual experiments
carried out at different time interval.
a
Reaction Conditions : Dialkylphosphite / diethylphosphine
oxide, CuCl2 and CsF were used in the mole ratio of 1:2:2 all
reactions were carried out at room temperature.
b Isolated yield.
Amongst the various solvents screened, acetone and ethyl
acetate afforded good yields (entries 1-6, table 1) and
minimum time required for the completion of reaction was
found to be 45 minutes (entries 6-8, table 1). Highest yield of
the desired product was obtained when CsF was taken as
fluorinating reagent (entries 6, 9-10, table 1). Although this
reaction is performed in single step, it proceeds in two
successive steps. In the first step, hydrogen of
dialkylphosphites is substituted by chlorine of CuCl in an
electrophilic displacement reaction. In the second step, the
chloride of dialkyl chlorophosphate is nucleophilically
displaced by fluoride. Putative reaction mechanism is
depicted in Scheme 2.
Caution! Dialkyl fluorophosphates are highly toxic
compounds and should be synthesized in efficient fume hood
by trained personals. High caution should be taken while
distilling the product and the waste must be decontaminated
by using 30% alkali solution.
The major advantage of this method is the operational
simplicity including the isolation of the product. The desired
product was isolated from the reaction mixture simply by
filtration of reaction mixture followed by concentration of the
solvent. The use of inorganic reagents helps in delivering
clean product without any organic impurities thus the process
required no purification step.
In conclusion, we have developed an efficient synthetic
method for the synthesis of dialkyl fluorophosphates at room
temperature. The electrophilic-nucleophilic displacement
reactions executed by the inorganic reagents resulted
fluorination of a variety of dialkyphosphite in excellent yield.

Supplementary data
1982, 21,294–1294; (d) T. Sierakowski, J.J. Kiddle,
Tetrahedron Lett. 2005, 46, 2215–2217.
10. Liu, N.; Mao, L.L.; Yang, B.; Yang, S.D. Chem.
Commun. 2014, 50, 10879-10882.
Experimental details and spectroscopic data of synthesized
compounds are presented in supporting information.
Acknowledgment
We thank Dr. Lokender Singh, Director DRDE, Gwalior, for
his keen interest and encouragement.
11. Zhou, Y.; Wang, G.; Saga,Y.; Shen, R.; Goto. M.; Zhao,
Y; Han, L.B. J.Org.Chem. 2010, 75, 7924-7927.
12. Typical experimental procedure: Dialkylphosphite, (0.10
mol) was added to a stirred suspension of two inorganic
reagent CuCl2 (0.20 mol) & CsF (0.20 mol) in acetone
(30 ml) at room temperature in one shot. The resulting
mixture was stirred at room temperature for 45 minutes
and monitored by GC-MS and 31P NMR. After
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 were 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.
Reference:
1. Gupta, A.K.; Acharya, J.; Pardasani, D.; Dubey,
D.K. Tetrahedron Lett. 2008, 49, 2232-2235.
2. (a) Saunders, B. C. Some Aspects of the Chemistry
and Toxic Action of Organic Compounds Containing
Phosphorus and Fluorine; Cambridge University
Press: Cambridge, 1957; (b) Majoral, J. P. New
Aspects in Phosphorus Chemistry I & II; Berlin
Heidelberg, 2000; (c) Wilson, B.W.; Walkar, C. R.
Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 3194; (d)
Metzler, D. E. In Biochemistry; Academic Press:
New York, 1950, Vol. 371; p 1013; (e) Bartlett, P.
A.; Lamdem, L. A. Bioorg. Chem.1986, 14, 356.
3. Furuya, T.; Ritter, T. Org. Lett. 2009,11,2860.
4. (a) Eto, M. Organophosphorus Pesticides: Organic
and Biological Chemistry; CRC press: USA, 1974;
(b) Engel, R. Chem. Rev.1977,77,349;(c) Kosolapoff,
G. M. In Organic Phosphorus Compounds; Wiley
Interscience: New York, 1950; Vol. 6, 319-510; (d)
Camps, F.; Coll, J.; Fabrias, G.; Guerrero, A.
Tetrahedron 1984,40,2871;(e) De Frank, J. J.
Applications of Enzyme Biotechnology.In Kelly, J.
W., Baldwin, T. O., Eds.; Plenum: New York, 1991;
pp165–180.
5. (a) Sikder, A. K.; Ghosh, A. K.; Jaiswal, D. K. J.
Pharm. Sci. 1993,82, 258-261; (b) Sikder, A. K.;
Pandey, K. S.; Jaiswal, D. K.; Dube, S. N.; Kumar,
D.; Hussain, K.; Bhattacharya, R.; Das Gupta, S. J.
Pharm. Pharmacol. 1992, 44, 1038-1040; (c) Eyer,
P. Toxicol. Rev. 2003, 22,165-190; (d) Kim, T. H.;
Oh, K. A.;Park, N. J.; Park, N. S.; Kim, Y. J.; Yum,
E. K.; Jung, Y. S. J. Appl.Biomed. 2006, 4, 67-72; (e)
Koelle, G. J. Pharmacol. Exp. Ther. 1946, 88,232-
237.
6. (a) Bartlett, P.A.; Lamdem, L.A. Bioorg.
Chem.1986, 14,356-357; (b) Engel, R. Chem. Rev.
1977, 77,349-367.
7. (a) Gerstenberger, M. R. C.; Haas, A. Angew Chem.,
Int. Ed. 1981, 20, 647-667; (b) Saville, B. J. Chem.
Soc. 1961,4624-4630; (c)Wozniak, L.A.; Chworos,
A.; Pyzowski, J.; Stec, W.J. J. Org. Chem. 1998, 63,
9109-9112; (d) Chworos, A.; Wozniak, L. A.
Tetrahedron Lett. 1999, 40, 9337-9340; (e) Roesky,
H. W. Inorg.Nucl. Chem. Lett.1969,5,891-895; (f)
Heuer, L.; Sell, M.; Schmutzler, R.; Schomberg, D.
Polyhedron 1987, 6,1295-1307.
8. (a) Dabkowski, W.; Cramer, F.; Michalski, J.
Tetrahedron Lett. 1987,28, 3561-3562; (b)
Konieczko, W. T.; Lopusinski, A.;Michalski, J.
Phosphorus, Sulfur, Silicon Relat. Elem. 1989, 42,
103-104; (c) Dabkowski, W.; Michalski, J.;
Skrzypczynski, Z. J Phosphorus, Sulfur,Silicon
Relat. Elem. 1986, 26, 321-326.
9. (a) O. Farooq, N. J. Chem.2000, 24, 81–84; (b) B.C.
Saunders, G.J. Stacey, J. Chem. Soc. 1948, 695–699;
(c) J.Michalski,A.Lopusinski, Angew.Chem.Int.Ed.

Where R= Alkyl group or Alkoxy group