A new microscale method for the conversion of phosphorus oxyacids to their fluorinated analogues, using cyanuric fluoride in solution and on solid support

Article abstract of DOI:10.1080/10426501003671445

Cyanuric fluoride, in solution or loaded onto a Wang resin, is successfully used as a fluorinating agent for phosphorus oxy acids. The reaction is very efficient with high yields and easy workup procedures, thereby in general generating products in quantitative yields. The cyanuric fluoride is proven suitable for micromolar scale synthesis of analytical standards, particularly in its resin-bound form. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003671445

Phosphorus, Sulfur, and Silicon, 185:2402–2408, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003671445
A NEW MICROSCALE METHOD FOR THE CONVERSION
OF PHOSPHORUS OXYACIDS TO THEIR FLUORINATED
ANALOGUES, USING CYANURIC FLUORIDE
IN SOLUTION AND ON SOLID SUPPORT
Rikard Wa¨rme and Lars Juhlin
Swedish Defence Research Agency, Division of CBRN Defence and Security,
Umea˚, Sweden
Cyanuric fluoride, in solution or loaded onto a Wang resin, is successfully used as a fluo-
rinating agent for phosphorus oxy acids. The reaction is very efficient with high yields and
easy workup procedures, thereby in general generating products in quantitative yields. The
cyanuric fluoride is proven suitable for micromolar scale synthesis of analytical standards,
particularly in its resin-bound form.
Keywords Cyanuric fluoride; micro scale; phosphorus fluoridates; solid phase synthesis
INTRODUCTION
In connection with the work concerning the identification of fluorinated phosphorus
compounds related to the Chemical Weapons Convention (CWC),1 there is an interest
in developing new and more effective synthetic methods appropriate for production on a
micromolar scale. Such methods would, if reliable, diminish the need for storage of the
compounds as analytical references. Instead, the compounds could be synthesized “on
demand” in the amounts and concentrations needed for the analytical work.
The most common production methods of phosphorus fluoridates are by halogen
exchange of the corresponding chloridate using, for instance, a fluoride ion.2–4 There are
also other methods to produce the fluoro analogues from various starting materials.5–7 By
avoiding the phosphorus chloridates as intermediates and directly synthesizing the phos-
phorus fluoridate, it is possible to bypass one reaction step and shorten the synthetic route.
Furthermore, halogen exchange reactions are equilibria, with which it is difficult to reach
completion, and the use of fluoride ions often involves salt slurries that make performance
on a small scale problematic. Since the phosphorus chloridates are very reactive, phos-
phorus anhydrides are often formed in a considerable amount during their production, if
synthesized from phosphorus oxy acids. This can also be seen in the fluorination of phos-
phorus oxyacids if a unit of the starting compound manages to react with a unit of product
(Scheme 1).
Received 10 December 2009; accepted 1 February 2010.
Address correspondence to Rikard Wa¨rme, Swedish Defence Research Agency, Division of CBRN Defence
and Security, Cementva¨gen 20, SE-90182 Umea˚, Sweden. E-mail: rikard.warme@foi.se
2402

SYNTHESIS OF FLUORINATED PHOSPHORUS COMPOUNDS
2403
O
O
O
P
O
P
R1
OH
R2
F
O
P
R1
P
R1
+
R1
HF
+
R2
R2
R2
R1 = methyl, isopropyl, butyloxy, phenyloxy
R2 = methyl, alkyloxy, phenyloxyl
Scheme 1 The formation of pyrophosphonates is sometimes a significant problem, hampering the yields.
A novel procedure for microscale synthesis of mono-alkylated phosphonic acids has
been developed.8 The phosphonates produced by this method can be efficiently transformed
using the same scale to the corresponding fluorinated analogues, if desired. The latter can be
accomplished with, for instance, fluoroenamines as previously shown,9 or the method that
is presented in this paper, cyanuric fluoride (CF).10 CF (2,4,6-trifluoro-1,3,5-triazine) is a
commercially available reagent that has been extensively used in preparation of carboxylic
fluorides, as well as for peptide coupling reactions.11–13 Although being hygroscopic, cor-
rosive, and toxic, the CF is relatively easily handled on micromolar scale, and furthermore,
the cyanuric acid (CA) that is formed due to hydrolysis is insoluble and precipitates in the
storage bottle, thus keeping the reagent relatively pure over time. High-yielding reactions
and convenient workup procedures are always sought by synthesis chemists, and these
factors become even more important the smaller the scales of the syntheses are. In this
context, the methods developed using CF match the requirements well.
RESULTS AND DISCUSSION
CF reacts with phosphorus oxy acids only to produce phosphorus fluoridates and
CA (Scheme 2). CA is a rather stable compound that is almost insoluble in many organic
solvents such as chlorinated hydrocarbons, which is taken advantage of in the following
method. During the reaction, CA precipitates and can therefore be easily removed by
filtration of the solution. All three equivalents of fluorine in the reagent are consumed
during the reaction, and our investigations indicate that the reactivity of CF increased after
the nucleophilic attack of the first oxy acid. This was supported by spectroscopic 19F NMR
data, where it was not possible to detect mono-fluoro analogue of the reagent in the reaction
mixture. Furthermore, the reactivity of the resin-bound CF was higher than the unbound CF
itself. The CF in solution reacts slowly with the phosphorus oxy acids at room temperature.
However, increasing the temperature to the interval 70–100◦C, depending on the starting
material, was found to accelerate the reaction sufficiently. Chlorinated solvents such as
chloroform, 1,2-dichloroethane, tetrachloroetylene, or 1,1,2,2-tetrachlorethane are the most
suitable for comparable substitution reactions, according to earlier investigations.9,14 The
final choice of solvent is of course dependent on the starting material and temperature
required for the specific reaction. Typically, a reaction time of approximately 20 h will
be sufficient to produce approximate yields of more than 95%, with the exception of
compounds with severe steric hindrance. For example, isopropylphosphonic acid with a
bulky O-alkyl group will need reaction times of at least 48 h to achieve acceptable yields.
The dialkyl phosphoric acids (phosphates) are found to be less reactive to CF than the
phosphinic or phosphonic acids and require even longer reaction times, if the reaction is
feasible at all. For instance, dibutyl phosphorofluoridates were successfully converted after

¨
2404
R. WARME AND L. JUHLIN
R1
O
F
O
P
O
P
OH
R2
F
3
R1
+
N
N
R2
N
NH
F
N
O
F
F
N
F
O
F
NH
HN
+
3
R1
P
R2
O
N
H
O
R1 = methyl, isopropyl, butyloxy, phenyloxy
R2 = methyl, alkyloxy, phenyloxy
Scheme 2 Schematic representation of the reaction of cyanuric fluoride and phosphorus oxy acid.
72 h of reaction, but we were unable to synthesize diphenyl phosphorofluoridate using
this method. It is not possible to synthesize methylphosphonic monofluoride exclusively
starting from methylphosphonic acid; the methylphosphonic difluoride is always formed to
some extent. An excess of reagent gives methylphosphonic difluoride quantitatively within
72 h. The reagent can be used in large excess without affecting the yields (∼5eq), and if
dry conditions are difficult to ensure, the amount of CF can be raised to compensate for
loss of reagent.
The progress of the reaction can be visually monitored by observing the CA precip-
itating from the reaction mixture. The various phosphorus oxy acids evaluated as starting
materials and the results of the fluorination reactions are presented in Table I. Another
important factor contributing to an effective method is the workup procedure, which in
this case is both simple and convenient. The workup will be described for three situations:
excess of reagent, deficit of reagent, and solid-phase chemistry. If CF is used excessively,
superfluous reagent can be removed by filtration through a small amount of citric acid
in a short column. The citric acid immediately reacts with the excess of reagent, and the
formed CA precipitates within the column. Filtration of the reaction mixture also removes
already precipitated CA in the reaction mixture, and the only compound still dissolved in
the solvent after the filtration is the product. If the starting material, solvent, or glassware
is contaminated with a small amount of water, there will possibly be a deficit of CF due
to hydrolysis of the reagent. As a consequence, some phosphorus oxy acid will remain in
the reaction mixture. The unreacted acid can be removed by promptly filtering the reaction
mixture through a small amount of alumina, although it is necessary to use a proper amount
of alumina. Otherwise, some product will be lost.
In order to improve the reagent and synthetic procedures even further, the potential
of CF as a polymer-supported reagent was investigated. To the best of our knowledge, this
is the first report demonstrating the use of solid-phase–supported CF in organic synthesis.
A Wang resin was used in accordance with the findings of Luo et al.,15 who used polymer-
supported cyanuric chloride in the synthesis of acyl chlorides. Contrary to these findings,
which indicated that a linker was needed in order to achieve acceptable yields, the reagent

SYNTHESIS OF FLUORINATED PHOSPHORUS COMPOUNDS
2405
Table I Synthesis of fluorinated analogues of phosphorus oxy acids
O
O
P
CF
OH
R2
F
R1
P
R1
1,2-dichloroethane
R2
R1 = methyl, isopropyl, butyloxy, phenyloxy
R2 = alkyloxy, phenyloxy, methyl, hydroxy
%
Yield
31P shift
(CDCl3)
R1
R2
Conversion (NMR)
JP–F
CH3
100
92
Quant
Quant
29.8
1048 Hz
CH3
29.6
1047 Hz
1054 Hz
CH3
CH3
100
100
Quant
Quant
30.3
29.1
28.4
1049 Hz
1047 Hz
59
89%a
34.9
1088 Hz
100
51
77%a
85%b
30%b
34.4
35.4
1086 Hz
1094 Hz
83
34.1
33.5
1087 Hz
1091 Hz
CH3
CH3
100
0
Quant
94%c
64.9
–8.7
990 Hz
978 Hz
0%
CH3
100
Quantc
24.1
1109 Hz
Reaction with CF (0.37 eq.) in dichloroethane at 100◦C during 23 h.
aOne additional unknown product containing phosphorus.
bIsopropylphosphonic mono- and difluoride were formed indicating cleavage of the alkyloxy group.
cFor difluoride, the reaction time must be at least 72 h.

¨
R. WARME AND L. JUHLIN
2406
can in this case be directly connected to the resin in a one-pot synthesis. There is no need to
use linkers in order to distance the reagent from the polymer to achieve good results. The
resin was characterized by IR spectroscopy, and by weighing the dried polymer, a yield
of 82% was determined. By using one of CF’s reactive sites to attach the reagent to the
polymer, two free sites are left to be consumed in the fluorination reactions. One of the
advantages is that the reactivity of this polymer-bound reagent is higher than that of the free
CF, resulting in the possibility of lowering the temperature. The enhanced reactivity makes
it possible to change the reaction medium to the more volatile chloroform, which is easier
to evaporate than 1,2-dichloroethane, after completion of the reaction. The phosphono
fluoridates (entry 1–8, Table I) were all afforded in quantitative yields. The most significant
byproduct in the reactions is phosphorus difluoride, which originates from contamination
of alkylphosphonic acid within the starting material. Hence, by starting with highly purified
phosphorus oxyacids, it is possible to synthesize small amounts of phosphonic fluoridates
of high quality by an immediate filtration of the reaction mixture followed by an evaporation
of the solvent.
EXPERIMENTAL
All phosphorus fluoridates were analyzed and characterized by NMR on a Bruker
Avance 500 spectrometer. The spectral data recorded were compared with previously
published data, including the following nuclei: 1H, 31P and 19F.3 The IR spectra of the resin
were recorded on a Thermo Nicolet Avatar 370. All equipment and solvents were dried
before use. The phosphonic acids, except for ethyl methylphosphonic acid, which was
obtained from Aldrich, were synthesized by the method of Petrov et al.16 The phosphinic
as well as the phosphoric acids were purchased from Aldrich and were used without
further purification. The purity of the phosphinic-, phosphonic-, and phosphoric acids was
at least 95% regardless of their origin. Chloroform was obtained from Fluka, and 1,2-
dichloroethane was obtained from BDH. All solvents were of p.a. quality and were dried
before use. DIPEA was purchased from Fluka and was freshly distilled before use. The
Wang resin was obtained from Fluka with a loading of 1 mmol/g, and the particle size was
200–400 mesh.
CAUTION: Phosphorus fluoridates are highly toxic, and the reaction must take place
in an effectively vented hood using the appropriate protecting equipment.
Synthesis of Resin-Bound Cyanuric Fluoride
Wang resin (250 mg, 0.25 mmol) was mixed with dry CHCl3 (6 mL). The reaction
flask was flushed with argon and sealed with a rubber septum. CF (250 µL, ∼7 eq) and
N-diisopropyl-ethylamine (DIPEA) (50 µL, ∼1 eq) were injected through a syringe. After
a reaction time of 24 h at room temperature, the resin was filtered and washed 3–4 times
with dried CHCl3 (3 mL). The resin was then dried thoroughly under reduced pressure and
characterized by IR. The yield of the reaction was 274 mg, 82%.
Synthesis of Phosphonofluoridates Using Cyanuric Fluoride
in Solution—General Procedure
Phosphorus oxyacid (50 µmol) was dissolved in of 1,2-dichloroethane (1 mL) in a
4 mL vial equipped with a magnetic stirring bar under argon atmosphere. CF (19 µmol,

SYNTHESIS OF FLUORINATED PHOSPHORUS COMPOUNDS
2407
active fluorine 1.14 eq) was added from a stock solution (CF 20% in CHCl3). The vial was
carefully sealed, and the solution was stirred in an oil bath at 100◦C for approximately 20
h. After cooling to room temperature, the reaction mixture was filtered through a small
column, size 5 mm in diameter, of citric acid (less than 0.25 g). The solvent was evaporated
under reduced pressure, and the product was isolated. For individual yields, see Table I.
Alternatively, if the reagent, due to improperly dried starting material, equipment, or
solvent, was consumed by hydrolysis, and the subsequent deficit of CF left some oxyacid
unreacted, this was removed by filtration of the reaction mixture through a 5 mm wide
column of alumina (typically 0.25 g). The solvent was evaporated, and the product isolated.
Synthesis of Phosphonofluoridates Using Polymer Supported Reagent,
General Procedure
To a solution of phosphonic acid (50 µmol) in CHCl3 (2.0 mL) in a 4 mL vial, CF-
resin (corresponding to CF 100–150 µmol, 2–3 eq.) was added, and the vial was sealed and
placed in an oil bath at 70◦C under slow stirring for 20 h. If the stirring was too vigorous, the
stirring bar might grind the polystyrene beads, which might lower the yield and obstruct the
workup procedure. When cooled to room temperature, the resin was removed by filtration,
and the filtrate was evaporated to give the product in quantitative yield.
Synthesis of Dimethylphosphinofluoridate
To a solution of dimethylphosphinic acid (10 mg, 0.11 mmol) in dry CHCl3 (1 mL),
CF (40 µmol) was added in one portion from a prepared stock solution (CF 20% in
CHCl3). After sealing the vial, the solution was stirred at 100◦C for 8 h. The workup was
identical to the one described above in the general procedure of the phosphonates. Dimethyl
phosphinofluoridate was afforded in quantitative yield.
Synthesis of Dibutyl Phosphorofluoridate
CF (19 µmol, 1.14 eq.) was added to a solution of dibutyl phosphoric acid (10 mg,
50 µmol) in dry CHCl3 (1 mL). The CF was added from a stock solution (CF 20% in
CHCl3) in order to facilitate the exact amount to be transferred. The reaction vessel was
sealed, and the temperature was set to 100◦C, whereupon the reaction was stirred for 72
h. The workup was identical to the one described above in the general procedure of the
phosphonates. The yield of dibutyl phosphorofluoridate achived was at this time 94%
Synthesis of Diphenyl Phosphorofluoridate
Even after a week at 100◦C in CHCl3, no fluorination was observed.
Synthesis of Methylphosphonic Difluoride
To a solution of methylphosphonic acid (10 mg, 0.1 mmol) in dry CHCl3 (1 mL),
CF (6.2 µL, active fluorine ∼2.2 eq.) was added in one portion. After sealing the vial, the
solution was stirred at 100◦C for 72 h. The workup was identical to the one described above
in the general procedure of the phosphonates. Methylphosphonic difluoride was afforded
in quantitative yield.

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R. WARME AND L. JUHLIN
2408
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